KAT6 Published Research Repository

This open-access original article in the American Journal of Medical Genetics Part A (2025;197:e64100) reports a case series and literature review focused on KAT6B-related disorders, a phenotypic continuum that includes Genitopatellar syndrome (GPS; OMIM #606170) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; OMIM #603736; variant of Ohdo syndrome). The authors present seven pediatric/young adult patients evaluated at two centers in Rome, Italy, all with de novo pathogenic or likely pathogenic monoallelic KAT6B variants identified by exome sequencing. Four patients were clinically classified as SBBYSS and three showed an intermediate phenotype with overlapping GPS and SBBYSS features. Five variants were novel, expanding the mutational spectrum. The paper highlights two features proposed as previously unreported manifestations in KAT6B disorders: partial penoscrotal transposition and hypopigmented macules.

KAT6B (lysine acetyltransferase 6B; MIM 605880) encodes a histone acetyltransferase within a transcription-regulating complex and is essential for human development, including neurogenesis and skeletogenesis. Historically, GPS and SBBYSS were considered distinct clinical entities, but accumulating overlap supports a single spectrum of "KAT6B disorders." SBBYSS is characterized by mask-like facies, blepharophimosis, ptosis, long thumbs and great toes, patellar hypoplasia or agenesis, and lacrimal duct anomalies, with frequent developmental delay, intellectual disability, and severe speech impairment. GPS is classically marked by agenesis or hypoplasia of the corpus callosum, microcephaly, severe psychomotor retardation, genital anomalies, renal anomalies (e.g., hydronephrosis, renal cysts), and contractures, along with patellar abnormalities.

Methods included extracting clinical data from records and applying published diagnostic feature sets to categorize each patient as SBBYSS, GPS, or intermediate. The authors also conducted a PubMed literature review, compiling 152 molecularly confirmed cases from 33 papers and calculating the frequency of 21 key clinical manifestations for SBBYSS versus GPS. Several "not otherwise specified" cases were re-categorized as intermediate phenotypes based on clinical criteria.

In the seven-patient cohort, core neurodevelopmental and craniofacial findings were prominent. Developmental delay and intellectual disability affected all assessable patients (6/7); severity ranged from mild to severe, with severe language impairment noted in multiple individuals. One previously published patient had additional behavioral and psychiatric features — including hetero-aggressive behavior, attention disorder, anxiety disorder, and sleep problems — not emphasized in the earlier report. Corpus callosum abnormalities were present in only one patient, consistent with the observation that such defects are uncommon in SBBYSS but frequent in GPS. Hypotonia occurred in 3/7, aligning with higher reported prevalence in SBBYSS than GPS. Microcephaly appeared in a minority (2/7). Seizures were not a major feature, though one infant had EEG focal abnormalities despite a normal early brain MRI.

Congenital anomalies showed variable involvement. Congenital heart defects were present in 2/7: one with patent ductus arteriosus and one with atrial septal defect plus mitral valve dysplasia. This is broadly consistent with the literature, where cardiac defects are common but not universal across KAT6B disorders, with atrial septal defect, ventricular septal defect, and patent ductus arteriosus being frequently reported.

The craniofacial phenotype was strongly supportive of SBBYSS across the cohort. Mask-like facies and blepharophimosis/ptosis were present in nearly all patients, alongside typical features such as sparse lateral eyebrows, hypertelorism, prominent cheeks, low-set ears, broad nasal bridge, bulbous nose, long philtrum, thin upper lip, and micro- or retrognathia. Dental anomalies were observed in several individuals, including dental diastemas and prominent upper central incisors. Palate anomalies were infrequent, with one case of soft palate cleft. Lacrimal duct anomalies occurred in one patient, and auricular pits were noted in two patients — a rare but previously described feature.

Musculoskeletal findings reflected the GPS end of the spectrum in some individuals. Contractures of the hips or knees, sometimes associated with clubfoot, were present in 4/7, including both SBBYSS and intermediate cases. Patellar hypoplasia was documented in two intermediate patients; patellar assessment was limited in the youngest infant due to the timing of ossification. Additional skeletal findings included scoliosis, camptodactyly, radial deviation, inwardly rotated feet, and narrow carpus.

Genital and endocrine findings were emphasized because they anchor the novel associations described. Genital anomalies affected 3/7, including cryptorchidism, micropenis, and hypospadias. One intermediate-phenotype patient had a complex genital phenotype including bilateral cryptorchidism, micropenis, hypospadias, and partial penoscrotal transposition, surgically corrected in infancy. The authors propose this as the first report of penoscrotal transposition in a patient with a KAT6B pathogenic variant, expanding the recognized urogenital spectrum. Endocrinological findings included delayed puberty in one patient and thyroid anomalies — including congenital hypothyroidism and subclinical hypothyroidism with anti-thyroperoxidase positivity — in others.

Gastrointestinal and feeding problems were common. Feeding difficulties occurred in over half of the cohort. One SBBYSS patient had imperforate anus requiring anoplasty, consistent with anal anomalies being uncommon overall but more frequent in GPS than SBBYSS in the compiled data.

Two patients exhibited pigmentary skin findings: one had multiple hypopigmented macules, and another had both achromic and hypopigmented macules. The authors state these are, to their knowledge, the first reported cases of hypopigmented macules in KAT6B disorders. In one of these patients, exome sequencing also identified a de novo ADAR variant (c.911G>A; p.Cys304Tyr) classified as a variant of uncertain significance. Because ADAR is linked to hereditary symmetric dyschromatosis (OMIM #127400), the authors discuss whether this could contribute to the skin findings, though lesion distribution was atypical and causality remains uncertain.

All seven patients had de novo KAT6B variants classified as pathogenic or likely pathogenic per ACMG criteria. The variants included frameshift, nonsense, missense, and splice-site changes, with clustering in exon 18 (four variants), plus variants in exons 16 and 17. Two variants were previously described, while five were novel. The study reinforces known genotype–phenotype correlations: GPS is often associated with proximal exon 18 truncating variants predicted to escape nonsense-mediated decay (suggesting a possible gain-of-function truncated protein), while SBBYSS is more often linked to distal exon 18 or other exons (suggesting haploinsufficiency). The authors also illustrate variability, noting that the same variant previously associated with classic SBBYSS corresponded to an intermediate phenotype in their infant, emphasizing incomplete predictability.

Overall, the article expands the clinical spectrum of KAT6B-related disorders through detailed phenotypic characterization, comparison to 152 literature cases, and identification of potential new features. It emphasizes frequent hallmark findings — blepharophimosis, ptosis, mask-like facies, developmental delay and intellectual disability, hypotonia, and contractures or patellar anomalies — while noting that some classic SBBYSS features such as lacrimal duct anomalies and patellar agenesis may be less prevalent than traditionally assumed. The authors conclude that KAT6B disorders are heterogeneous with common intermediate phenotypes, presenting challenges for diagnosis and genetic counseling. They also highlight DNA methylation episignatures for KAT6A/KAT6B as emerging diagnostic adjuncts, particularly in unresolved cases or for interpretation of variants of uncertain significance.

Background:

Arboleda-Tham syndrome (ARTHS), caused by likely pathogenic or pathogenic variants in the KAT6A gene, is characterized by developmental delay, distinctive facial dysmorphic features, and congenital cardiac anomalies. ARTHS warrants consideration in the differential diagnosis of neonates exhibiting unexplained cardiac arrhythmias, seizures, and dysmorphic features, although neonatal-onset manifestations remain underrecognized.

Case:

We report two Chinese patients with KAT6A variants diagnosed in the neonatal period who presented with life-threatening manifestations. Two unrelated neonates presented with severe cardiac arrhythmias or seizures within the first month of life, in association with congenital heart defects and developmental delay. Whole-exome sequencing (WES) identified two de novo KAT6A variants: a novel splice-site variant (c.3352 + 1G>C) in patient 1, who developed supraventricular tachycardia at 23 days of life, and a previously reported missense variant (c.4645G>A; p. Gly1549Ser) in patient 2 with seizures onset at 11 days. Both patients exhibited complex congenital heart disease (Patient 1: VSD, ASD and PDA; Patient 2: PFO and PDA), developmental delay, and characteristic dysmorphic features consistent with ARTHS.

Conclusion:

This report highlights the critical role of genomic sequencing in the diagnostic evaluation of neonates with unexplained cardiac arrhythmias or seizures. WES should be considered in neonates exhibiting severe early-onset multisystem involvement and dysmorphic features to investigate potential KAT6A variants. These findings substantially expand the phenotypic spectrum of ARTHS by documenting severe neonatal manifestations and contribute to a deeper understanding of KAT6A-related phenotypic variability.

The MYST family histone acetyltransferase gene, KAT6B (MYST4, MORF, QKF) is mutated in two distinct human congenital disorders characterised by intellectual disability, facial dysmorphogenesis and skeletal abnormalities; the Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome and Genitopatellar syndrome. Despite its requirement in normal skeletal development, the cellular and transcriptional effects of KAT6B in skeletogenesis have not been thoroughly studied. Here, we show that germline deletion of the Kat6b gene in mice causes premature ossification in vivo, resulting in shortened craniofacial elements and increased bone density, as well as shortened tibias with an expanded pre-hypertrophic layer, as compared to wild type controls. Mechanistically, we show that the loss of KAT6B in mesenchymal progenitor cells promotes transition towards an osteoblast-progenitor state with upregulation of gene targets of RUNX2, a master regulator of osteoblast development and concomitant downregulation of SOX9, a critical gene in chondrocyte development. Moreover, we find that compound heterozygosity at Kat6b and Runx2 loci partially rescues the reduction in ossification of Runx2 heterozygous, but not homozygous mice, suggesting that KAT6B may limit the action of RUNX2, possibly through a role in maintaining progenitors in an undifferentiated state. Moreover, our results show that KAT6B has essential roles in regulating the expression of a large number of genes involved in skeletogenesis and bone development.

Background and objective

Mutations in the KAT6A gene, which encodes a histone acetyltransferase, have been linked to an autosomal dominant neurodevelopmental disorder known as the Arboleda-Tham syndrome. The clinical symptoms of this disorder are nonspecific and pose challenges to accurately characterizing the condition based solely on these symptoms. This study aimed to establish a definitive diagnosis in three patients with intellectual disability and multiple congenital anomalies, and to elucidate the genotype-phenotype correlation based on the existing literature.

Participants and methods

In this study, we investigated three probands with severe intellectual disability, global developmental delay, hypotonia, gait disturbance, microcephaly, scoliosis, abnormal heart morphology, strabismus, gastrointestinal dysmotility, and abnormal facial shape, using karyotype analysis, multiplex ligation-dependent probe amplification, and whole exome sequencing. We also conducted a comprehensive literature review of previously reported cases.

Results

The karyotype analysis and Multiplex ligation-dependent probe amplification results were normal. Whole exome sequencing revealed three novel de novo mutations, c.3712G > T (p.Glu1238*), c.3561 C > A (p.Cys1187*), and c.1069 C > T (p.Arg357*), in the KAT6A gene (NM_006766.5). The heterozygous variants were verified by Sanger sequencing and were not present in either parent.

Conclusions

In this study, we describe three cases of de novo KAT6A variants that were identified for the first time in Iran. Our results expand the understanding of the clinical features associated with Arboleda-Tham syndrome and validate the effectiveness of whole-exome sequencing to rapidly and accurately determine the etiology of such disorders. Furthermore, our literature review demonstrated close genotype-phenotype correlations associated with KAT6A and Arboleda-Tham syndrome.

This Cureus case report focuses on genitopatellar syndrome (GPS) associated with a novel variant in the KAT6B gene and uses the patient’s phenotype and genotype to support “spectrum delineation” across KAT6B-related disorders. Genitopatellar syndrome is a rare genetic syndrome classically characterized by patellar aplasia or hypoplasia, flexion contractures of the lower limbs (especially knees and hips), congenital anomalies of the genitourinary tract, intellectual disability or developmental delay, and characteristic craniofacial features. KAT6B (lysine acetyltransferase 6B) is a key gene involved in chromatin remodeling and transcriptional regulation, and pathogenic variants in KAT6B are known to cause a phenotypic spectrum that includes genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS, sometimes historically linked to Ohdo syndrome). The article’s central message is that novel KAT6B variants continue to expand the mutational landscape and reinforce that GPS and SBBYSS are overlapping entities within a KAT6B spectrum rather than strictly separate disorders.

The report likely presents a single patient (or small family) with clinical features consistent with genitopatellar syndrome and documents genetic testing that identified a previously unreported (novel) KAT6B variant. In many published GPS/SBBYSS reports, the variant is a de novo truncating variant (nonsense, frameshift, or splice-altering) in KAT6B, frequently in the gene’s terminal exons, and the paper likely discusses how variant position and predicted effect correlate with phenotype. The case presentation typically emphasizes prenatal history (including possible polyhydramnios, reduced fetal movement, or congenital anomalies seen on ultrasound), birth history, postnatal growth, developmental milestones, dysmorphology findings, musculoskeletal anomalies, and genitourinary findings. Because genitopatellar syndrome is often associated with severe lower-limb involvement, the clinical narrative may describe absent or underdeveloped patellae, knee flexion contractures, clubfoot, hip dislocation, or other orthopedic problems requiring early specialist care. The “genito” component of genitopatellar syndrome commonly includes ambiguous genitalia, cryptorchidism, hypospadias, uterine anomalies, or renal/urinary tract anomalies; the authors likely describe imaging such as renal ultrasound, voiding studies, or pelvic ultrasound to document structural findings.

Craniofacial and neurologic features are often highlighted in KAT6B-related disorders. The paper likely describes facial gestalt such as blepharophimosis, ptosis, a flat or broad nasal bridge, a thin upper lip, micrognathia, or other dysmorphic features. Developmental delay is common, with variable degrees of intellectual disability, hypotonia, feeding difficulty, and speech delay. The authors may note associated anomalies that have been reported across the KAT6B spectrum, such as congenital heart disease, thyroid dysfunction, hearing loss, dental anomalies, or central nervous system findings. If present, these additional findings are often used to emphasize phenotypic overlap with Say-Barber-Biesecker-Young-Simpson syndrome, which can include mask-like facies, blepharophimosis/ptosis, lacrimal duct anomalies, and broader multisystem involvement.

A major focus of the discussion is likely the concept of “spectrum delineation.” In contemporary clinical genetics, KAT6B-related disorders are increasingly understood as a continuum in which genitopatellar syndrome and SBBYSS represent ends of a phenotypic spectrum rather than discrete diagnoses. The article likely compares the patient’s features to classic GPS and classic SBBYSS features, identifying which findings align more strongly with GPS (for example, patellar aplasia/hypoplasia and prominent knee flexion contractures) and which findings overlap with SBBYSS (for example, facial features like blepharophimosis and ptosis, or other congenital anomalies). The authors probably review prior literature and explain that the same gene, KAT6B, can yield variable expressivity and variable severity depending on the variant type, variant location, and possibly nonsense-mediated decay or dominant-negative effects.

The genetics section likely outlines the diagnostic approach: the patient’s presentation prompted genetic evaluation, and molecular testing (such as whole exome sequencing, a congenital anomaly gene panel, or targeted KAT6B testing) revealed the novel KAT6B variant. The authors presumably applied standard variant interpretation criteria (often American College of Medical Genetics and Genomics/ACMG guidelines) to classify the variant as pathogenic or likely pathogenic based on predicted loss of function, absence from population databases, de novo status, and phenotype match. The paper likely emphasizes the value of genetic testing in confirming genitopatellar syndrome, enabling anticipatory management, and providing reproductive counseling regarding recurrence risk (which is generally low if de novo, but not zero due to possible germline mosaicism).

The clinical management implications are often emphasized in case reports of rare syndromes. The article likely recommends multidisciplinary care for genitopatellar syndrome and KAT6B-related disorders, including orthopedics for contractures and patellar anomalies, urology/nephrology for genitourinary anomalies, cardiology if congenital heart disease is present, endocrinology for thyroid or growth concerns, ENT/audiology for hearing issues, ophthalmology for ptosis/blepharophimosis, and developmental pediatrics with early intervention services for developmental delay. Feeding therapy and nutrition support may be discussed if the patient had feeding difficulties or failure to thrive. The authors may also mention surveillance strategies, such as monitoring renal function, tracking growth and development, assessing airway and sleep in the presence of craniofacial anomalies, and planning orthopedic interventions or physical therapy.

In supporting spectrum delineation, the report likely concludes that documenting novel KAT6B variants is important for refining genotype–phenotype correlations. The patient’s phenotype may show blended features of genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome, reinforcing that clinicians should consider KAT6B testing when encountering key “search-friendly” features such as patellar aplasia, knee flexion contractures, genitourinary anomalies, craniofacial dysmorphism (including blepharophimosis and ptosis), global developmental delay, and multiple congenital anomalies. The novelty of the variant contributes to the growing catalog of pathogenic KAT6B variants and supports the view that KAT6B-related disorders represent a spectrum with overlapping phenotypes. The paper likely calls for further case reporting and database sharing to improve recognition, diagnosis, counseling, and clinical management of genitopatellar syndrome and other KAT6B spectrum disorders.

If you paste the article (or even just the Abstract + Case Presentation + Discussion), I can produce an accurate, detailed 1,000‑word summary with the exact patient findings, exact KAT6B variant, and the authors’ specific conclusions while keeping it highly search-friendly with relevant keywords (genitopatellar syndrome, KAT6B gene, novel variant, genotype-phenotype correlation, Say-Barber-Biesecker-Young-Simpson syndrome, KAT6B spectrum, congenital anomalies, patellar aplasia, flexion contractures, genitourinary anomalies, developmental delay).

Objective: This study aims to report a severe phenotype of Arboleda-Tham syndrome in a 20-month-old girl, characterized by global developmental delay, distinct facial features, intellectual disability. Arboleda-Tham syndrome is known for its wide phenotypic spectrum and is associated with truncating variants in theKAT6A gene.

Methods: To diagnose this case, a combination of clinical phenotype assessmentand whole-exome sequencing technology was employed. The genetic analysis involved whole-exome sequencing, followed by confirmation of the identified variant through Sanger sequencing.Results: The whole-exome sequencing revealed a novel de novo frameshift mutation c.3048del (p.Leu1017Serfs*17) in the KAT6A gene, which is classified as likely pathogenic. This mutation was not found in the ClinVar and HGMD databases and was not present in her parents. The mutation leads to protein truncation or activation of nonsense-mediated mRNA degradation. The mutation is located within exon 16, potentially leading to protein truncation or activation of nonsense-mediated mRNA degradation. Protein modeling suggested that the denovo KAT6A mutation might alter hydrogen bonding and reduce protein stability, potentially damaging the protein structure and function.Conclusion: This study expands the understanding of the genetic basis of Arboleda-Tham syndrome, highlighting the importance of whole-exome sequencing in diagnosing cases with varied clinical presentations. The discovery of the novel KAT6A mutation adds to the spectrum of known pathogenic variants and underscores the significance of this gene in the syndrome's pathology.

Keywords: Arboleda-Tham syndrome, de novo truncating variants, facial dysmorphism, globaldevelopmental delay, KAT6A

Intellectual disability (ID) affects ~2% of the population and ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is KAT6A, whose mutations cause KAT6A syndrome, with ID as a common clinical feature. However, the underlying molecular mechanism remains unknown. Here, we find that KAT6A deficiency impairs synaptic structure and plasticity in hippocampal CA3, but not in CA1 region, resulting in memory deficits in mice. We further identify a CA3-enriched gene Rspo2, encoding Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Deletion of Rspo2 in excitatory neurons impairs memory formation, and restoring RSPO2 expression in CA3 neurons rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice. Collectively, our results demonstrate that KAT6A-RSPO2-Wnt signaling plays a critical role in regulating hippocampal CA3 synaptic plasticity and cognitive function, providing potential therapeutic targets for KAT6A syndrome and related neurodevelopmental diseases.

Ng et al. (2024) in Orphanet Journal of Rare Diseases report one of the first prospective, performance-based characterizations of the neuropsychological phenotype associated with KAT6A (Arboleda–Tham) syndrome, a rare Mendelian disorder of the epigenetic machinery caused by pathogenic variants in KAT6A, a histone acetyltransferase in the MYST family involved in chromatin regulation and transcription. Prior work has established that intellectual disability and severe speech and language impairment — often leaving individuals minimally verbal — are common, with some studies suggesting more severe outcomes in late-truncating variants in exons 16–17. However, much of the cognitive and behavioral phenotype has remained unclear because many published studies rely on retrospective chart review or caregiver and clinician ratings rather than standardized cognitive testing. This study addresses that gap by integrating performance-based neuropsychological measures and caregiver-report inventories, and by exploring early genotype–phenotype trends comparing protein-truncating variants versus missense variants.

The sample included 15 individuals with molecularly confirmed KAT6A syndrome (8 female; mean age approximately 10.3 years; range 4–20), recruited through the KAT6 Foundation. Genetic review confirmed variant type: 12 participants had truncating variants (10 late-truncating in exons 16–17 and 2 early-truncating in exons 1–15) and 3 had missense variants. Most variants were classified as pathogenic and largely de novo.

Caregivers completed standardized rating scales spanning executive function, autism-related traits, behavior problems, and adaptive skills, including the BRIEF-2/BRIEF-P/BRIEF-A for everyday executive functioning, the SRS-2 for autism spectrum features, the CBCL for internalizing and externalizing behaviors, and the ABAS-3 for adaptive functioning across conceptual, social, and practical domains. Performance-based cognition was assessed using measures targeting nonverbal and receptive domains with minimal verbal output demands: the DAS-II Special Nonverbal Composite, NEPSY-II subtests for visuospatial perception and receptive language comprehension, the Beery VMI-6 for visual-motor integration, and the PPVT-5 for receptive vocabulary.

Caregiver-reported diagnostic history (available for 14 of 15 participants) indicated high rates of neurodevelopmental diagnoses: intellectual disability in approximately 86%, ASD in approximately 29%, and ADHD in approximately 29%, with every participant carrying at least one of these diagnoses. All participants had received speech and language therapy and occupational therapy, and approximately 87% had received physical therapy.

Across standardized testing, the sample showed global cognitive impairment, with performance typically more than two standard deviations below normative means on many measures. A key finding was that nonverbal cognition was not relatively preserved: group analyses did not find meaningful differences between nonverbal cognitive performance on the DAS-II and receptive language performance on the PPVT-5 and NEPSY-II Comprehension of Instructions. In other words, the cognitive phenotype includes equally impaired nonverbal reasoning and receptive language, countering earlier impressions that receptive language might be spared. Visuospatial perception as measured by the NEPSY-II Arrows subtest appeared comparatively less impaired at the group level than other domains, suggesting a potential relative strength in certain spatial perception skills, though variability and task completion limitations constrain strong conclusions.

Caregiver inventories revealed a distinctive behavioral and adaptive pattern. On the ABAS-3, the General Adaptive Composite was very low, with conceptual and practical domains especially impaired; the social adaptive domain was also low but relatively stronger than the other two, indicating that everyday social skills may be less affected than communication, academics, self-direction, and daily living. On the SRS-2, many participants showed clinically elevated autism-related features, particularly restricted interests and repetitive behaviors, which emerged as a prominent characteristic. Social motivation, by contrast, tended to be less elevated than other SRS-2 scales, suggesting that while autistic features — especially rigidity and repetitive behaviors — are common, many individuals exhibit a strong social drive and interest in interaction rather than social withdrawal. On the BRIEF, the Global Executive Composite fell in an at-risk range on average, with working memory standing out as the most prominent daily-life challenge and cognitive flexibility also frequently problematic. Emotional control was notably within typical limits for most participants and represented a relative strength. Behavior problem ratings on the CBCL were generally within typical ranges, with low levels of externalizing behaviors and no participants meeting clinical cutoffs for externalizing problems, suggesting low frequency of severe behavioral dysregulation despite substantial cognitive and adaptive needs.

Exploratory analyses comparing truncating and missense variants suggested a trend toward lower cognitive performance in truncating variants across several tests, but statistical significance emerged only for a limited subset, specifically DAS-II Special Nonverbal Composite scores and DAS-II Pattern Construction. Other measures including receptive language did not show significant differences, likely reflecting the small missense sample and limited power. Caregiver-report inventories did not show detectable differences between truncating and missense groups, implying that day-to-day behavioral and adaptive profiles may be broadly similar even when performance-based cognition differs. Contrary to some prior retrospective reports, early-truncating and late-truncating variants yielded comparable neuropsychological profiles in this sample. One practical observation was that individuals with late-truncating variants more often could not complete certain cognitive tests due to comprehension or task-understanding limits, though the authors caution against firm conclusions given small subgroup sizes.

The authors conclude that the cognitive phenotype of KAT6A syndrome reflects global neurodevelopmental impact rather than language impairment alone, and that clinicians should plan supports beyond speech therapy. The behavioral phenotype is characterized by high rates of repetitive behaviors and inflexibility, significant adaptive deficits, and notable weaknesses in working memory and cognitive shifting, yet with relative strengths in emotional control, behavior regulation, and social motivation. Limitations include small sample size, wide age range, reliance on caregiver-reported diagnostic history, and the challenge that some participants could not complete standardized tasks. The authors emphasize the need for larger, longitudinal, and interdisciplinary research incorporating neurobiological measures such as EEG and MRI, and alternative low-motor and low-language methods such as eye-tracking, to better capture cognition in minimally verbal individuals. They also recommend cross-syndrome comparisons with related disorders of the histone and epigenetic machinery — including KAT6B disorders and Kabuki syndrome — to clarify shared pathways and inform potential future clinical trials.

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b^+/–), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b^+/– mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b^+/– mice and partially reversed gene expression changes in Kat6b^+/– cortical neurons. Both compounds improved sociability in Kat6b^+/– mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.

KAT6B and KAT6A belong to the MYST family of lysine acetyltransferases, and regulate gene expression via histone modification. Although both proteins share similar structure and epigenetic regulatory functions, it remains unclear if KAT6A/6B mutation disorders, both very rare conditions, yield the same neurocognitive presentation and thus benefit from similar treatment approaches. This study provides a preliminary overview of neuropsychological functioning of 13 individuals with KAT6B disorder (Mean age = 9.01 years, SD = 5.46), which was compared to that of a recently published sample of 15 individuals with KAT6A syndrome (Mean age = 10.32 years, SD = 4.12). Participants completed a neuropsychological test battery to assess non-verbal cognition, and caregivers completed a series of standardized rating inventories to assess daily behavioral functioning. Results reveal those with KAT6B disorders present with severe adaptive deficits (92.3%) and autism-related behaviors (83.3%), juxtaposed with relatively low concerns with externalizing behaviors (7.6%), a pattern shared by the KAT6A group. Those with KAT6B disorders present with high levels of autistic features, including reduced affiliative interest, whereas social motivation is less affected within the KAT6A group. Overall, the levels of impairment in nonverbal cognition and receptive language were comparable among those with KAT6B disorders, a trend also seen in the KAT6A group. In brief, KAT6B and KAT6A disorders yield analogous neuropsychological profiles. Findings implicate common molecular pathophysiological mechanisms for these epigenetic disorders, such that similar therapies may have shared effect across diseases.

Arboleda-Tham syndrome (ARTHS, MIM 616268) is a rare genetic disease, due to a pathogenic variant of Lysine (K) Acetyltransferase 6A (KAT6A) with autosomal dominant inheritance. Firstly described in 2015, ARTHS is one of the more common causes of undiagnosed syndromic intellectual disability. Due to extreme phenotypic variability, ARTHS clinical diagnosis is challenging, mostly at early stage of the disease. Moreover, because of the wide and unspecific spectrum of ARTHS, identification of the syndrome during prenatal life rarely occurs. Therefore, reported cases of KAT6A syndrome have been identified primarily through clinical or research exome sequencing in a gene-centric approach.

In order to expands the genotypic and phenotypic spectrum of ARTHS, we describe prenatal and postnatal findings in a patient with a novel frameshift KAT6A pathogenic variant, displaying a severe phenotype with previously unreported clinical features.

This clinical report describes marked phenotypic variability in a Danish family with an inherited KAT6A frameshift variant, expanding the known spectrum of KAT6A syndrome, also known as Arboleda-Tham syndrome (ARTHS; OMIM #616268). ARTHS is a syndromic neurodevelopmental disorder typically characterized by developmental delay and intellectual disability — especially speech and language delay — with frequent additional findings including hypotonia, autism spectrum disorder and behavioral problems, eye anomalies, cardiac defects, gastrointestinal issues, movement disorder, microcephaly, and seizures. Emerging literature suggests additional associations with immune dysfunction and pituitary anomalies. Most pathogenic KAT6A variants are de novo; inherited variants are rare, and previously reported familial cases largely involved missense variants, while inherited truncating variants were typically linked to parental or germline mosaicism. This report is notable for documenting an inherited truncating variant with variable expression across three related individuals, including a mildly affected child with normal cognitive assessment and a functioning adult carrier.

The genetic finding central to the report is a heterozygous, previously unreported KAT6A variant: NM_006766.5:c.2710dup (p.(Glu904Glyfs*12)), a frameshift predicted to introduce a premature stop codon. It is absent from gnomAD v4.1.0, not previously listed in HGMD (2024.2), and classified as likely pathogenic using ACMG criteria. Trio-based exome analysis derived from whole genome sequencing identified the variant in the proband and her father; subsequent segregation testing confirmed the same variant in her younger brother. The father's parents tested negative, suggesting the variant arose de novo in the father and was then transmitted in an autosomal dominant pattern to both children. The authors emphasize that this family illustrates how intrafamilial variability in KAT6A syndrome can be as broad as variability observed across unrelated cases, and highlights the importance of not filtering out inherited variants when parental phenotypes appear mild.

Patient 1, the proband, is a 9-year-old girl with a more classic and complex ARTHS presentation. Prenatal ultrasound showed intrauterine growth restriction and signs suggestive of fetal compromise, leading to delivery by cesarean at 35 weeks and 6 days. Early gross motor milestones were largely normal. Cardiac evaluation revealed a ventricular septal defect and patent ductus arteriosus, with PDA closure by catheterization in infancy. She had frequent early childhood hospitalizations for upper respiratory infections and asthmatic bronchitis, and recurrent otitis media requiring tympanostomy tubes. Hearing was transiently concerning but later normalized.

Her principal neurodevelopmental phenotype involved profound expressive language delay with milder receptive delay; at age three her spoken vocabulary was limited to "yes" and "no." Standardized testing indicated mild-to-moderate intellectual disability particularly affecting executive function, with social and motor skills relatively preserved. Brain MRI did not show structural malformations but detected a large suprasellar arachnoid cyst approximately 4.6 cm in size, later treated by endoscopic fenestration. She developed frequent headaches and sleep disturbance responsive to melatonin, and intracranial pressure monitoring showed episodic elevations treated with acetazolamide. Ophthalmologic findings included left exotropia (surgically corrected), hypermetropia, astigmatism, and mild vision impairment. Dysmorphic facial features included mild unilateral ptosis, short up-slanted palpebral fissures, hypertelorism, epicanthus, thin lips, and mild joint hypermobility.

A particularly novel finding was premature pubarche and precocious puberty developing around age 7 years and 10 months, with positive GnRH testing and treatment initiated to slow pubertal progression. The authors note this is the first reported case of premature pubarche in KAT6A syndrome and discuss possible contributions from prior intracranial pathology near the pituitary region, though pituitary anomalies were not confirmed on MRI. The patient also experienced multiple traumatic fractures over two years; bone density and bone markers were normal, and the fracture rate was ultimately considered within expected range given her activity level and pubertal growth.

Patient 2, a 7-year-old boy and full sibling, showed a milder phenotype. He was delivered prematurely at 33 weeks and 3 days due to mild intrauterine growth restriction. Motor development was normal and early childhood was largely uneventful aside from a single febrile seizure. Developmental assessment around age three revealed severe expressive speech delay — he was essentially nonverbal at assessment — while receptive language, motor skills, and cognitive performance were reported as age-appropriate. Cardiac and hearing evaluations were normal. He showed postnatal poor growth with height tracking around −2 to −2.5 SD, with mildly low IGF-1, though stable growth led to no further endocrine workup. At age seven he remained significantly speech delayed with fewer than 30 words and limited to two-word sentences, but overall cognition and motor development were noted as appropriate. He represents an additional case in which cognitive assessment appears normal despite a pathogenic KAT6A variant, aligning with recent reports of normal intellect in a small subset of individuals with KAT6A syndrome and underscoring potential ascertainment bias in earlier cohorts.

The report also mentions a stillborn sister delivered at 36 weeks and 2 days with persistent intrauterine growth restriction and placental pathology suggesting maternal vascular malperfusion. Fetal microarray was normal and the family declined further testing, so no direct link to KAT6A could be established.

Patient 3, the 36-year-old father, demonstrates adult survivorship and relatively high functional independence alongside subtle neurodevelopmental challenges. He showed dysmorphic facial features similar to his children. He required individualized education supports, did not complete final middle-school exams, and did not pursue high school, though he now works full time in subsidized employment as a carpenter. He reports difficulties with executive functioning, particularly planning and managing multiple tasks simultaneously. He is fully verbal, suggesting substantial long-term improvement or compensation in speech and communication compared with his children's early minimal-verbal status. In adulthood he experienced recurrent episodes consistent with myocarditis, including fever, chest and shoulder pain, elevated inflammatory markers and troponin, transient reduced ejection fraction, pericardial effusion, and conduction abnormalities including AV block and sinus pauses, with pacemaker implantation under consideration. The authors discuss this in the context of proposed immune dysfunction in KAT6A syndrome but acknowledge the findings are nonspecific and immunologic evaluation was not performed.

In the discussion, the authors integrate their observations with known genotype–phenotype correlations. Prior studies suggest late-truncating variants in exons 16–17 correlate with more severe intellectual disability, while early-truncating variants in exons 1–15 may be associated with milder outcomes. The family's variant lies in the early region, consistent with the mild cognitive impact in Patient 2 and the relatively functional adult outcome in Patient 3, while still allowing moderate intellectual disability in Patient 1. The report reinforces that expressive language impairment is a core and persistent feature of KAT6A syndrome, yet long-term verbal prognosis can improve, as illustrated by the father's adult verbal abilities and by published cohorts in which a subset of individuals become verbal despite early severe delay. Novel or uncertain associations highlighted include premature pubarche, headaches with intracranial pressure issues related to an arachnoid cyst, and recurrent fractures with normal bone density.

Overall, this family-based report broadens the recognized phenotypic spectrum of KAT6A syndrome by demonstrating that inherited protein-truncating frameshift variants can present with widely variable expressivity, ranging from minimal-verbal language profiles and moderate intellectual disability to normal cognitive assessment and relatively mild adult functional impairment. The findings have implications for genetic counseling, recurrence risk assessment, consideration of inherited variants during diagnostic filtering, and clinical management focused on communication support, neurodevelopmental monitoring, multisystem evaluation, and awareness of possible later-onset complications.

Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in Lysine(K) acetyltransferase 6A (KAT6A). ARTHS is clinically heterogeneous and characterized by several common features including intellectual disability, developmental and speech delay, hypotonia and affects multiple organ systems. KAT6A is highly expressed in early development and plays a key role in cell-type specific differentiation. KAT6A is the enzymatic core of a histone-acetylation protein complex, however the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n=8) and control (n=14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused by KAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23%(14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posterior HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene-body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles of KAT6A in a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types.

Keywords: Arboleda-Tham syndrome; HOX genes; KAT6A; Multiomics; Rare genetic disorder; chromatinopathies.

Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268). The analysis revealed the presence of de novo pathogenic variant in KAT6A gene, a nucleotide c.3385C>T substitution that introduces a premature termination codon (p.Arg1129*). The need for straight multidisciplinary collaboration and accurate clinical description findings (bowel obstruction/megacolon/intestinal malrotation) was emphasized, together with the utility of CES in establishing an etiological basis in clinical and genetical heterogeneous conditions. Therefore, considering the phenotypic characteristics, the condition’s rarity and the reviewed literature, we propose additional diagnostic criteria that could help in the development of future clinical diagnostic guidelines. This was possible thanks to objective examinations performed during the long follow-up period, which permitted scrupulous registration of phenotypic changes over time to further assess this rare disorder. Finally, given that different genetic syndromes are associated with distinct genomic DNA methylation patterns used for diagnostic testing and/or as biomarker of disease, a specific episignature for ARTHS has been identified.

Keywords: KAT6A, Arboleda-Tham syndrome, clinical exome sequencing, methylation studies, episignature, SNP array

De novo, rare, and genomic variants in the KAT6A gene have been associated with cases of intellectual disability with speech/language impairment. The pathogenic variants of KAT6A gene can produce the KAT6A enzyme inefficiently, faulty, or in inappropriate quantity. In order to search for compounds able to modulate the KAT6A gene expression, we treated primary human osteoblasts with molecules structurally similar to bisphenol A, a potentially toxic compound known as an upregulator of KAT6A gene expression. We further demonstrated that much safer compounds, such as luteolin and 17 α hydroxyprogesterone, could induce the upregulation of KAT6A gene in human osteoblasts.

Epigenetics, one mechanism by which gene expression can change without any changes to the DNA sequence, was described nearly a century ago. However, the importance of epigenetic processes to neurodevelopment and higher order neurological functions like cognition and behavior is only now being realized. A group of disorders known as the Mendelian disorders of the epigenetic machinery are caused by the altered function of epigenetic machinery proteins, which consequently affects downstream expression of many genes. These disorders almost universally have cognitive dysfunction and behavioral issues as core features. Here, we review what is known about the neurodevelopmental phenotypes of some key examples of these disorders divided into categories based on the underlying function of the affected protein. Understanding these Mendelian disorders of the epigenetic machinery can illuminate the role of epigenetic regulation in typical brain function and can lead to future therapies and better management for a host of neurodevelopmental and neuropsychological disorders.

This original article in Molecular Genetics & Genomic Medicine (2023;11:e2265) reports detailed clinical and molecular findings in six Polish patients with a KAT6B-related disorder, highlighting marked clinical heterogeneity across individuals who share recognizable dysmorphic features but differ in severity and organ involvement. The paper focuses primarily on Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; OMIM 603736) and its overlapping presentations with genitopatellar syndrome (GPS), reinforcing the growing view that these conditions represent a KAT6B spectrum disorder rather than strictly separable entities.

SBBYSS is a rare autosomal dominant multiple congenital anomaly syndrome caused by heterozygous pathogenic variants in KAT6B (chromosome 10q22.2). KAT6B encodes a highly conserved histone acetyltransferase of the MYST family, involved in epigenetic regulation important for development, especially of the skeletal and nervous systems. Classic SBBYSS features include characteristic facial dysmorphism (often described as mask-like facies), blepharophimosis and ptosis, hypotonia, feeding difficulties, developmental delay and intellectual disability, and skeletal findings such as long thumbs and great toes and classically patellar hypoplasia or agenesis. GPS (OMIM 606170) is generally more severe and includes major skeletal and genital anomalies. Increasing reports of intermediate or overlapping phenotypes complicate genotype-based prediction and support a unified KAT6B-related disorders framework.

The authors outline previously proposed diagnostic criteria and summarize reported genotype–phenotype correlations linking variant position in KAT6B to predicted clinical outcomes. They also discuss proposed molecular mechanisms, including whether truncated transcripts escape nonsense-mediated mRNA decay and yield truncated proteins — often associated with more severe GPS-like presentations — versus variants leading to nonsense-mediated decay or haploinsufficiency, which are more often associated with SBBYSS or milder phenotypes. These mechanisms remain incompletely validated and may not fully explain observed variability.

DNA from peripheral blood leukocytes underwent next-generation sequencing, including targeted enrichment and/or whole-exome sequencing approaches, with alignment to GRCh38/hg38. Variants were classified using ACMG/AMP criteria and confirmation was performed using amplicon deep sequencing. All six individuals carried de novo pathogenic variants in KAT6B (NM_012330.4): one previously known synonymous variant affecting splicing and five novel truncating variants. The known variant, c.3147G>A (p.Pro1049=) in exon 16, was previously demonstrated to induce aberrant splicing with partial exon 16 loss at the RNA level, resulting in a frameshift and protein truncation. The novel variants were mostly truncating changes in exon 18: frameshift deletions and duplications c.3852_3864del, c.4026dup, c.5012del, and c.5819del, as well as a nonsense change c.4455dup. All variants were absent from population databases and were scored as pathogenic under ACMG/AMP criteria.

Despite variable severity, all patients had recognizable facial dysmorphism and developmental and speech delay. Most had hypotonia, ocular abnormalities (including hypermetropia, astigmatism, nystagmus, and strabismus), and long thumbs. Many showed blepharophimosis and skeletal or knee involvement. Notably, patellar abnormalities in this cohort were generally less severe than the classic aplasia or hypoplasia described in SBBYSS; instead they included patellar dysplasia, habitual dislocation, subluxation, or milder knee malalignment such as genu valgum. This supports expanding the expected orthopedic spectrum in KAT6B-related disorders.

The six probands are summarized as follows. Proband 1 was a male who died at age three. He had prenatal bilateral hydronephrosis, reduced fetal movements, multiple urologic surgeries, severe feeding problems, profound developmental delay, hypotonia, hypothyroidism, bilateral sensorineural hearing loss, recurrent infections, lacrimal duct anomalies, agenesis of the corpus callosum with ventriculomegaly, a patent foramen ovale, long thumbs, clubfeet, nail dysplasia, knee contractures, shoulder exostoses, bilateral cryptorchidism, and bifid scrotum. Proband 2 was a male who died at age six years and eight months. He had preterm birth with neonatal respiratory compromise requiring mechanical ventilation, severe malnutrition, global developmental delay, seizures, long thumbs, camptodactyly, genu valgum, habitual patellar dislocation and subluxation, bilateral cryptorchidism, hypospadias, scrotal hypoplasia, hydronephrosis, hypothyroidism, agenesis of the corpus callosum, a ventricular septal defect, and multiple ocular findings. Proband 3 was a 24-year-old woman with a milder SBBYSS presentation, including typical facial dysmorphism, blepharophimosis, long thumbs, bilateral patellar subluxation, hypotonia, global developmental and speech delay, hypermetropia, cleft uvula, malocclusion, and hypothyroidism. Her variant (c.5819del) was one of the most distal truncating variants reported in KAT6B. Proband 4 was a male with classic facial features including downslanting palpebral fissures, bulbous nose, long philtrum, thin upper lip, and microretrognathia, along with drooling, long thumbs, genu valgum, flat feet, overlapping toes, hearing loss, hypermetropia, and bilateral cryptorchidism. His variant was the known splicing change c.3147G>A. Proband 5 was a 15-month-old girl with neonatal hypotonia, microcephaly, feeding problems, high palate, hearing loss, ocular findings, congenital heart disease (atrial and ventricular septal defects), agenesis of the corpus callosum, hypothyroidism, and café-au-lait spots, but no clear skeletal or patellar anomalies at the time of assessment. Proband 6 was a 20-year-old woman with feeding and swallowing difficulties, blepharophimosis, long fingers, clubfeet, radioulnar synostosis, bilateral patellar subluxation, delayed tooth eruption, multicystic kidneys, a spontaneously closed atrial septal defect, variable muscle tone, developmental and speech delay, astigmatism, nystagmus, and bilateral hearing loss.

The authors compare their findings to prior reviews, noting high rates of neurodevelopmental delay, hypotonia, hearing loss, ocular findings, congenital heart defects, hypothyroidism, and brain anomalies — notably corpus callosum agenesis in three patients — consistent with published literature. However, classic SBBYSS skeletal expectations, especially severe patellar aplasia or hypoplasia, were not consistently present. Milder patellar dysplasia and instability predominated, and one patient lacked obvious skeletal or patellar findings altogether, reinforcing the concept of broader phenotypic variability in KAT6B-related disorders.

Crucially, the genotype–phenotype analysis did not fully support previously proposed correlations based solely on affected codon ranges. Several patients clinically resembled SBBYSS despite variants predicted to align with GPS or intermediate categories, emphasizing that variant position alone may be insufficient for precise clinical prognostication. The authors note that KAT6B episignatures — distinct DNA methylation patterns for GPS versus SBBYSS reported in prior studies — may help define molecular phenotypes and explain intra-gene variability, and they propose future work applying methylation profiling to refine diagnosis and correlation in KAT6B spectrum disorders.

In a recent issue of this journal, a meta-analysis of 18 studies found that exome sequencing (ES) afforded an incremental diagnostic yield of 21% over chromosomal microarray analysis (CMA)/karyotyping in fetuses with congenital heart defect (CHD), with yields of 11% for isolated CHD and 37% for CHD associated with extracardiac anomalies¹. The study addressed the issue of considering ES in apparently isolated cases of CHD. Diagnostic workup of isolated CHD is not uniform in prenatal centers, as most offer quantitative fluorescence polymerase chain reaction (QF-PCR) and CMA when a cardiac anomaly is detected, with some adding a small panel of selected cardiac genes but using ES only when a syndrome is suspected. We report on two fetuses with prenatally detected mild CHD, in which ES identified a rare monogenic syndrome, KAT6A or Arboleda–Tham syndrome, which would not have been detected by other genetic techniques.

A 30-year-old primigravida was referred to our tertiary fetal medicine unit with suspicion of right aortic arch on the 20-week scan. Ultrasonography showed a double aortic arch, small thymus, isolated left-sided cleft palate with intact lip and a bulbous nose (Figure 1). The initial impression was of 22q11 deletion, but amniocentesis was performed and CMA results were normal. After genetic counseling, trio ES was performed and the sequencing data were analyzed for variants in a select panel of genes

associated with fetal anomalies. This analysis showed a de-novo heterozygous deletion of exons 13–17 within the KAT6A gene, which was classified as pathogenic as per the joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)². The classification was assigned based on the deletion of multiple exons in a loss-of-function-intolerant gene, absence of similar deletions in population databases, previous reporting of multiple loss-of-function variants in the deleted region in patients with KAT6A syndrome³ and the de-novo occurrence. The specific codes applied were 2E (PVS1_vs), 3A and 4C. The finding was confirmed with quantitative PCR (qPCR) in the fetus. Next-generation sequencing and qPCR performed on parental samples (without a positive control due to exhaustion of fetal DNA) showed no evidence of the deletion, consistent with it being de novo in the fetus. To the best of our knowledge, this specific variant has not been reported previously. At 31 + 6 weeks, additional features of brachycephaly and trigonocephaly were noted. Following detailed counseling, the patient requested termination of pregnancy due to the increased risk of syndromic intellectual disability, which was performed at 32 weeks.

Our second case was a 38-year-old woman, gravida 5 para 1, who was referred for an early anomaly scan at 12 + 5 weeks after in-vitro fertilization. Her history included, in addition to the delivery of one healthy child, an ectopic pregnancy, an intrauterine fetal demise at 21 weeks and an early pregnancy termination due to anencephaly. The early anomaly scan showed a normal nuchal translucency thickness but abnormal drainage of the ductus venosus into the inferior vena cava and a left superior vena cava with a muscular ventricular septal defect (Figure 2). Chorionic villus sampling revealed a normal karyotype and CMA detected a non-pathogenic variant, namely a 104-kb heterozygous duplication in the pseudoautosomal region-1, covering SHOX, which would not explain the ultrasound abnormalities observed. At 16 weeks, cardiac findings were confirmed and trio ES was performed, which revealed a heterozygous de-novo mutation, c.4663A > G (p.Ser1555Gly), in exon 17 of the KAT6A gene, which fulfilled the ACMG criteria PS2, PM1, PM2, PP3 and BP1-Class 4 and was classified as likely pathogenic². Kennedy et al. reported a similar variant, p.Ser1555Arg, in a cohort of 76 cases with Arboleda–Tham syndrome³. Subsequent examination at 18 + 5 weeks confirmed the cardiac findings in addition to bilateral pyelectasis and a head shape suggestive of brachycephaly with early signs of possible craniosynostosis (Figure 2b). After genetic counseling, the patient opted for pregnancy termination.

In both cases, patients declined postmortem examination as the genetic diagnosis was sufficient for counseling. As a result, detailed postnatal phenotypes were not obtained.

KAT6A syndrome was first described in 2015 simultaneously by Arboleda et al.⁴ and Tham et al.⁵ as a monogenic syndrome of intellectual disability associated with abnormalities of the face, eyes, head shape and heart. The KAT6A gene is located on the short arm of chromosome 8, band 8p11.21. According to https://kat6a.org, there are 334 registered individuals with KAT6A syndrome at the time of writing and, to the best of our knowledge, our two cases are the first to be reported prenatally. Cardiac anomalies have been reported in up to 70% of patients with KAT6A syndrome, some of whom require surgery³. Patients have been reported to have an abnormal head shape, including microcephaly, brachycephaly and craniosynostosis^3-6, as observed in our cases. Of special interest is Case 1, in which the phenotypic features resembled a 22q11 deletion; it has been reported that KAT6A regulates expression of the TBX1 gene, leading to this similarity^{7, 8}. Most cases in the literature were diagnosed using ES in individuals with an intellectual disability rather than a cardiac anomaly³. From a prenatal point of view, even with ultrasound findings of mild CHD, as in our cases, ES can be of benefit to families in addition to QF-PCR and CMA and is more likely to identify a diagnosis than is a small gene panel. In addition, we recommend adding the KAT6A gene to the cardiac gene panel offered in many genetic laboratories.

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Keywords: Episignatures, Neurodevelopmental disorders, DNA methylation, Epigenetics, Clinical diagnostics

Objective

To explore the genetic etiology for a child featuring mental retardation and speech delay.

Methods

Clinical data of the child was collected. DNA was extracted from peripheral blood samples of the child and members of his pedigree. Whole exome sequencing was carried out for the child, and candidate variants were verified by Sanger sequencing. Prenatal diagnosis was provided for his mother upon her subsequent pregnancy.

Results

The child has mainly featured mental retardation, speech delay, ptosis, strabismus, photophobia, hyperactivity, and irritability. Whole exome sequencing revealed that he has harbored a pathogenic heterozygous variant of the KAT6A gene, namely c.5314dupA (p.Ser1772fs*20), which was not detected in either of his parents. The child was diagnosed with Arboleda-Tham syndrome. The child was also found to harbor a hemizygous c.56T>G (p.Leu19Trp) variant of the AIFM1 gene, for which his mother was heterozygous and his phenotypically normal maternal grandfather was hemizygous. Pathogenicity was excluded. Prenatal diagnosis has excluded the c.5314dupA variant of the KAT6A gene in the fetus.

Conclusion

The heterozygous c.5314dupA (p.Ser1772fs*20) variant of the KAT6A gene probably underlay the Arboleda-Tham syndrome in this child. Above finding has enabled genetic counseling and prenatal diagnosis for this pedigree.

The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases.

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.

Smith and Harris (2021) in Brain Sciences report a detailed phenotype description of KAT6A syndrome (also known as Arboleda–Tham syndrome, ARTHS; MIM#616268), focusing on sleep, behavior, and adaptive function. KAT6A syndrome is classified as a Mendelian Disorder of the Epigenetic Machinery (MDEM) and is characterized by developmental delay and intellectual disability alongside profound expressive language impairment, often with additional medical features such as microcephaly, neonatal hypotonia, gastroesophageal reflux, constipation, feeding difficulties, congenital heart defects, behavioral concerns, and sleep disturbance. The authors emphasize that refined neurobehavioral phenotyping is important for future clinical trials and outcome measures, particularly because some MDEMs show postnatal reversibility in preclinical models.

The study aimed to further characterize adaptive behavior, maladaptive behavior, and sleep problems in individuals with genetically confirmed KAT6A syndrome, and to explore potential genotype–phenotype correlations. The cohort included 26 participants aged 3 to 35 years (mean approximately 11 years), recruited from the Kennedy Krieger Institute clinic and via the KAT6A Foundation, with eligibility restricted to English-speaking families. Data were collected using parent-report instruments: the Adaptive Behavior Assessment System, Third Edition (ABAS-3) for conceptual, social, and practical domains and a General Adaptive Composite score; the Achenbach Child Behavior Checklist and Adult Behavior Checklist (CBCL/ABCL) for internalizing, externalizing, and total problems as well as DSM-oriented scales for depressive, anxiety, and ADHD problems; and the Modified Simonds and Parraga Sleep Questionnaire (MSPSQ) for sleep-related behaviors and medical sleep symptoms over the prior month.

KAT6A variants were grouped by type: late-truncating (primarily variants in exons 16–17), early-truncating, and missense/splice-site. Of the 26 individuals, 13 were male, and the study reports nine variants not previously published. Most participants had protein-truncating loss-of-function variants: 19 had late-truncating frameshift or nonsense variants, 3 had early-truncating variants, 2 had frameshift variants leading to early truncation, 3 had novel likely pathogenic missense variants, and 1 had a splice-site variant. While earlier work suggested late-truncating variants might be associated with more severe intellectual disability, this study did not find statistically significant differences across variant groups in adaptive function, behavior, or sleep, though small subgroup sizes limited inference.

A central finding was that adaptive function was extremely low across the cohort, without clear domain-specific strengths. Mean ABAS-3 standard scores (population mean 100, SD 15) were in the "extremely low" range for all domains — conceptual, social, practical, and the General Adaptive Composite. Across participants, approximately 74% of the 96 domain and composite standard scores reported were two or more standard deviations below the population mean, underscoring substantial functional support needs. The authors found no correlation between age and adaptive function in this sample. This adaptive profile supports the clinical recommendation that individuals with KAT6A syndrome require robust educational, community, and daily living supports, and that adaptive limitations may be pervasive even when some cognitive or receptive abilities are relatively stronger than expressive language.

Despite profound adaptive impairment and significant sleep disturbance, parent-reported behavioral problems were surprisingly low relative to expectations for intellectual disability cohorts. Only 18% of potential problem-area scores on the CBCL/ABCL reached clinical significance. Mean levels of internalizing problems, externalizing problems, and total problems were generally below clinical thresholds, and DSM-oriented scales for depressive, anxious, and ADHD problems showed a similar pattern. The study found no correlation between age and behavior, and no correlation between adaptive functioning and behavior, suggesting that lower adaptive skills did not necessarily translate to higher reported psychopathology or disruptive behaviors in this group. This low-problem behavior profile is a notable contribution to KAT6A syndrome characterization and suggests that for many families, core challenges center more on communication, learning, daily living skills, and sleep than on aggression or severe behavioral dysregulation. The authors recommend further work using direct behavioral assessment tools beyond caregiver checklists.

Sleep disturbance emerged as a major clinical issue. Using MSPSQ-derived definitions, the authors report high rates across numerous domains: approximately 80% of participants moved around a lot in bed several times per month or more (restless sleep); about 52% had multiple or prolonged awakenings (sleep maintenance problems); about 36% took an hour or more to fall asleep (prolonged sleep initiation); about 56% had bruxism; about 72% of those aged seven and older had daytime drowsiness or somnolence; about 72% of those aged seven and older had enuresis; about 64% used medication for sleep; about 68% had sought advice or treatment for sleep; and about 60% of parents perceived their child's sleep as problematic.

Importantly, sleep-disordered breathing did not appear to explain most of these complaints. Snoring was reported in about 24% of participants and apnea in about 12%, suggesting that while obstructive sleep apnea can occur, the broader sleep phenotype likely involves behavioral insomnia, restlessness, parasomnia-like symptoms, circadian disruption, or other mechanisms beyond apnea alone. Clinically, this supports taking a detailed sleep history that goes beyond snoring and apnea, and considering further evaluation with actigraphy or polysomnography. The study also found that most sleep variables did not correlate with adaptive functioning or behavior; however, sleep-disordered breathing specifically was associated with higher total, internalizing, and externalizing behavior problems, consistent with the broader pediatric sleep literature.

Overall, Smith and Harris conclude that KAT6A syndrome is characterized by a triad of severely impaired adaptive functioning across conceptual, social, and practical domains; a high prevalence of clinically meaningful sleep problems including restless sleep, insomnia symptoms, bruxism, daytime sleepiness, enuresis, and frequent medication use; and unexpectedly low rates of maladaptive behavior on standard measures, aside from associations with sleep-disordered breathing. For clinicians, the paper highlights the need to prioritize adaptive supports, individualized education planning, and comprehensive sleep assessment and treatment not limited to obstructive sleep apnea. For researchers, it identifies sleep and adaptive function as key targets for future natural history studies and potential therapeutic trials, while suggesting that broad behavior problem counts may be less sensitive as primary outcome measures. Limitations include small sample size, wide age range, reliance on parent-report tools, lack of cognitive testing data, and absence of sleep control groups, leading the authors to call for larger cohorts and objective sleep measurement to refine the KAT6A neurobehavioral and sleep phenotype.

Background

This study aimed to explore the effect of KAT6A on the decreased stemness of aging bone marrow-derived mesenchymal stem cells (BMSCs) and its potential mechanism.

Methods

The acetylation level and KAT6A expression of BMSCs from the young (YBMSCs) and the old (OBMSCs) were examined. Gain- and loss-of-function experiments were performed to determine the effect of KAT6A on BMSC proliferation, colony formation, and osteogenic differentiation. The effect of KAT6A on Nrf2/ARE signaling pathway was investigated after KAT6A inhibition in YBMSCs or overexpression in OBMSCs, and the role of Nrf2/ARE signaling pathway on stemness was examined by investigating proliferation, colony formation, and osteogenic differentiation. Further in vivo study was performed to explore osteogenesis ability of OBMSCs after modulation of KAT6A and Nrf2/ARE pathway through cell sheet technology.

Results

The acetylation level and KAT6A expression of OBMSCs were decreased, and KAT6A downregulation resulted in decreased proliferation, colony formation, and osteogenic differentiation of OBMSCs. Mechanically, KAT6A was found to regulate Nrf2/ARE signaling pathway and inhibit ROS accumulation in OBMSCs, thus promoting proliferation, colony formation, and osteogenic differentiation of OBMSCs. Further study demonstrated that KAT6A could promote osteogenesis of OBMSCs by regulating Nrf2/ARE signaling pathway.

Conclusions

Downregulation of KAT6A resulted in the decreased stemness of OBMSCs by inhibiting the Nrf2/ARE signaling pathway.

Graphical abstract

KAT6A was downregulated in aging bone marrow-derived mesenchymal stem cells (BMSCs), and downregulation of KAT6A resulted in Nrf2/ARE signaling pathway inhibition and ROS accumulation, thus leading to decreased stemness of aging BMSCs.

A nonverbal 3-year-old male with a complex past medical history was referred to pediatric neurosurgery for evaluation of Chiari I malformation. A full clinical evaluation suggested that the "Chiari" was a secondary change caused by craniocerebral disproportion that was the result of delayed pan-sutural craniosynostosis. Given his unknown cause of craniosynostosis, whole-exome sequencing (WES) was performed. WES revealed a de novo, somatic mosaic variant in the KAT6A gene. This report discusses importance of keeping a broad differential in the setting of referral for Chiari I malformation and presents a unique case of craniosynostosis. Additionally, it emphasizes the value of utilizing genetic testing for complex craniofacial cases with unknown causes to provide clinical answers and guide clinical management.

This open-access original article in Molecular Genetics & Genomic Medicine (2021;9:e1809) reports novel variants in the KAT6B spectrum of disorders, expanding knowledge of clinical manifestations and molecular mechanisms. The authors describe 20 individuals with pathogenic or likely pathogenic variants in KAT6B (Lysine Acetyltransferase 6B, also known as MORF or MYST4; MIM #605880), expanding both the phenotypic spectrum and genotype–phenotype correlations across KAT6B-related disorders, including Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; MIM #603736), Genitopatellar syndrome (GPS; MIM #606170), intermediate presentations, and "not otherwise specified" cases. The study also explores genetic counseling experiences and uses CRISPR-engineered cell models with RNA-seq, ATAC-seq, gene ontology, and pathway analysis to probe molecular mechanisms.

Clinical information was collected from 12 institutions via a targeted questionnaire capturing multisystem features historically associated with GPS and SBBYSS plus additional findings. The cohort ranged in age from 6 months to 28 years and was 75% female. Nineteen cases had not been previously published. Testing methods included whole-exome sequencing and targeted panels across multiple laboratories. Across the 20 individuals, the authors identified 17 protein-truncating variants — 13 frameshift and 4 nonsense — with 10 novel variants accounting for 50% of cases. Variants were reported on transcript NM_012330.3 and clustered largely in exon 18, within the transcriptional control region, particularly the acidic domain and nearby serine/methionine-rich regions. KAT6B is a MYST-family histone acetyltransferase involved in transcriptional activation and H3K23 acetylation, and the mutated region was predicted to be intrinsically disordered, suggesting disruption of complex binding and transcriptional regulation rather than a simple structural-domain effect.

Individuals were initially categorized by clinicians as GPS, SBBYSS, or intermediate, then reclassified using published criteria into GPS (n=7), SBBYSS (n=8), intermediate (n=3), and not otherwise specified (n=2). A notable recurrent mutation hotspot was c.3769_3772delTCTA (p.Lys1258Glyfs*13), found in four GPS individuals with highly overlapping severe multisystem phenotypes. The cohort reinforces that variant position can help guide subtype tendencies — GPS variants more often in distal exon 17 and proximal exon 18, SBBYSS variants in distal exon 18 and exons 13–17 — yet substantial overlap supports a gene-based KAT6B-spectrum disorder framing.

Developmental delay and intellectual disability occurred in 100% of the cohort, with profound or severe language impairment essentially universal among those assessed. Motor delay was prominent, with 85% showing delayed mobility or being non-ambulatory at data collection, and hypotonia was equally frequent at 85%. Microcephaly was common (70%), especially in GPS, and agenesis or hypoplasia of the corpus callosum was present in about half of those assessed (9/18), strongly enriched among GPS and intermediate cases. Seizures occurred in 25%, often in the context of structural brain abnormalities. A clinician-reported happy or stable disposition was noted in a subset, though the study acknowledges variability and under-ascertainment.

Visual and hearing impairments were frequent and underlined as important for management. Approximately 75% had some form of visual impairment, including cortical visual impairment, optic nerve hypoplasia, and strabismus. Hearing loss was present in roughly one-third, spanning sensorineural, conductive, and unspecified patterns. The co-occurrence of hearing loss with visual problems was highlighted as not well characterized in previous reports.

Craniofacial features overlapped across subtypes but retained recognizable patterns. SBBYSS-enriched features included mask-like facies, blepharophimosis, and ptosis, yet these were also reported in non-SBBYSS cases, illustrating the spectrum effect. Common cross-group findings included broad or prominent nasal bridge, bulbous nose, micrognathia or retrognathia, and low-set, posteriorly rotated, or dysplastic ears. Palatal anomalies including high-arched and cleft palate occurred in a substantial minority. Dental anomalies — including delayed eruption, hypoplastic or peg-shaped teeth, overcrowding, and underbite — were reported in several individuals and may be more prevalent than previously appreciated.

Skeletal anomalies were universal in the cohort. Characteristic findings included absent or hypoplastic patellae (notably agenesis in GPS), contractures of the knees, hips, and clubfoot (prominent in GPS and intermediate cases), and long thumbs and great toes (particularly consistent in SBBYSS). A major expansion of the clinical spectrum was the higher-than-expected frequency of joint hypermobility, subluxations and dislocations, and especially fractures, reported in approximately 44% of those assessed and sometimes involving the femur or tibia. The authors propose possible contributory factors including low bone density, osteopenia, ossification delay, and altered pain sensitivity, and recommend consideration of bone health surveillance in this population.

Feeding difficulties occurred in 95% of the cohort (19/20), with frequent gastrostomy dependence, reflux and GERD, vomiting, constipation, and occasional malrotation requiring surgical intervention. Respiratory problems were also common, with laryngomalacia and respiratory distress occurring in a majority; some individuals required oxygen, tracheostomy, or BiPAP, or had chronic lung disease often associated with prematurity. Cardiac malformations were frequent at approximately 75%, most often atrial septal defect, ventricular septal defect, and patent ductus arteriosus, supporting routine cardiac evaluation in diagnosed patients.

Renal and urogenital findings aligned with subtype tendencies but overlapped. All GPS individuals had hydronephrosis, and some had persistent renal structural abnormalities, recurrent urinary tract infections, and surgical interventions. Genital anomalies were common overall (60%), with cryptorchidism in all males in the cohort and additional anomalies such as hypospadias and scrotal hypoplasia; some females, especially those with GPS, had labial hypoplasia. Hypothyroidism appeared more frequent than some prior reports and was sometimes transient. Prenatal findings were common, with 78% showing scan anomalies including polyhydramnios, hydronephrosis, clubfoot, congenital heart defects, and agenesis of the corpus callosum.

A dedicated survey assessed how families engage with genetic counselors. Most families met with a counselor, typically in one to four sessions, and 56% received the diagnosis before age two — a time when prognosis and longitudinal expectations are hardest to define. Families often sought guidance on prognosis, future complications, and recurrence risk. The dominant counseling challenge was marked phenotypic heterogeneity combined with limited natural history data, particularly when an individual's features were milder or different from published cases, complicating anticipatory guidance and support-group alignment.

To explore molecular mechanisms, the authors created CRISPR-Cas9 edited HEK293T cell lines with truncating indels in exon 3 of KAT6B. ATAC-seq identified surprisingly few differential chromatin accessibility peaks, while RNA-seq and pathway analysis provided further insight into the transcriptional consequences of KAT6B disruption, with gene ontology analysis highlighting pathways relevant to development and epigenetic regulation. The authors note that because the engineered truncations were early relative to many patient variants, and because HEK cells are pseudotriploid requiring careful allele-level characterization, the functional findings should be interpreted with appropriate caution and contextualized against patient variant data.

Overall, this study substantially expands the recognized clinical and molecular landscape of KAT6B-related disorders, highlights underappreciated features such as fractures, bone health concerns, dental anomalies, and the co-occurrence of visual and hearing impairment, and underscores the phenotypic continuum that challenges strict GPS versus SBBYSS classification. The genetic counseling findings illustrate the real-world complexity families face, and the functional genomics work provides a foundation for further mechanistic investigation.

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.

This letter to the editor in the Journal of Genetics and Genomics expands the genetic landscape of Rett syndrome (RTT; OMIM 312750) by proposing KAT6A (also known as MOZ/MYST3; OMIM 616268) as an important alternative genetic etiology in individuals diagnosed with Rett syndrome, atypical Rett syndrome, or Rett-like phenotypes who test negative for MECP2 (OMIM 300005). Rett syndrome is an X-linked, severe, progressive neurodevelopmental disorder predominantly affecting females, typically characterized by an initial period of apparently normal development followed by regression. Using the revised clinical diagnostic criteria proposed by Neul et al. (2010), patients are classified as classic RTT or atypical RTT, with "RTT-like" used when partial phenotypic overlap is present but criteria are insufficient for a formal diagnosis. Classic RTT requires developmental regression followed by stabilization and all four main criteria: partial or complete loss of purposeful hand skills, partial or complete loss of acquired spoken language, gait abnormalities, and stereotypic hand movements. Atypical RTT requires at least two main criteria plus at least five supportive criteria. While approximately 97% of classic RTT and 86% of atypical RTT cases have pathogenic MECP2 variants, a subset of affected individuals remain genetically undiagnosed; a minority are explained by pathogenic variants in CDKL5 and FOXG1.

The authors frame this work within the broader concept that disorders affecting transcriptional regulation and epigenetic control — particularly chromatin regulators — can converge on RTT-like neurodevelopmental phenotypes. MeCP2 is a global epigenetic regulator that binds methylated CpG dinucleotides and influences transcriptional repression and activation, chromatin remodeling, and RNA splicing. KAT6A is a member of the MYST family of histone acetyltransferases and acetylates histone H3 at lysines H3K9 and H3K14, a process critical for chromatin regulation and neurodevelopment. Previous animal and cellular studies show that KAT6A disruption can impair neurogenesis and craniofacial development, providing a mechanistic bridge to human developmental disorders.

The study reports seven unrelated individuals aged 3 years 8 months to 21 years 6 months, identified as RTT or RTT-like, each carrying a different de novo heterozygous late-truncating KAT6A variant. Two individuals were considered compatible with atypical RTT under Neul's revised diagnostic criteria, while five were classified as RTT-like — initially diagnosed with KAT6A-related intellectual disability syndrome but found on reassessment to have substantial RTT-like features. Two of the RTT-like cases were identified via systematic reanalysis of a previously published cohort of 76 individuals with KAT6A syndrome. The authors' consistent message is that clinicians evaluating RTT or RTT-like presentations, especially when MECP2 testing is negative, should consider next-generation sequencing approaches and include KAT6A in analysis pipelines.

All seven variants are monoallelic, protein-truncating (nonsense or frameshift), clustered in the final exon (exon 17) of KAT6A, and absent from gnomAD. Variants include nonsense changes such as c.3385C>T p.(Arg1129*), c.3820G>T p.(Glu1274*), c.3631_3632del p.(Val1211*), and c.3661G>T p.(Glu1221*), as well as frameshift variants including c.3399_3400dup p.(Lys1134Argfs14), c.3377del p.(Ser1126Phefs8), and c.4254_4257del p.(Glu1419Trpfs*12). All were classified as pathogenic (class 5) by ACMG guidelines. KAT6A shows strong loss-of-function intolerance (pLI = 1.0 in gnomAD). Because these truncating variants occur in the last exon, they are predicted to escape nonsense-mediated mRNA decay, potentially producing truncated proteins with dominant-negative or gain-of-function effects — a mechanistic hypothesis that may help explain phenotypic variability among individuals with late-truncating KAT6A variants.

Clinically, the cohort demonstrates overlapping features between KAT6A syndrome and Rett or Rett-like presentations. All individuals exhibited global developmental delay, severe intellectual disability, profound speech delay or absence of speech, abnormal muscle tone, and sleep problems. Most never acquired spoken language, meaning clear regression of acquired language — central to classic RTT — was generally not observed; however, in at least one case regression could be interpreted as loss of babbling, consistent with Neul's definition. Only two individuals had a documented period of regression followed by stabilization or recovery and met atypical RTT thresholds. Common systemic issues included feeding difficulties, gastroesophageal reflux, and constipation. One case also had intestinal malrotation with recurrent bowel obstruction.

A key differentiator from classic RTT noted by the authors is the presence of facial dysmorphism typical of KAT6A-related intellectual disability, which in several individuals prevented classification as atypical RTT despite strong phenotypic overlap. Reported dysmorphic features across the cohort included thin upper lip, prominent nasal bridge, dental abnormalities, and variably broad nasal tip, bitemporal narrowing, high-arched palate, and philtrum defects. Congenital cardiac defects were prominent (in 4/7), including atrial septal defect, ventricular septal defect, patent ductus arteriosus, patent foramen ovale, pulmonary artery stenosis, and mitral valve abnormalities — features frequently associated with KAT6A syndrome and less characteristic of RTT due to MECP2 variants. Several individuals also had recurrent infections, and neuroimaging findings were variable, including delayed myelination, craniosynostosis, and Arnold–Chiari type I malformation. Ocular and visual abnormalities and genitourinary issues were also reported in some cases.

The authors note that RTT is less commonly diagnosed in males due to X-linked inheritance assumptions, but this cohort includes three males, with one meeting atypical RTT criteria. This supports careful phenotyping irrespective of sex and reinforces that autosomal dominant chromatin disorders like KAT6A syndrome can produce RTT-like clinical pictures in both females and males.

Supporting evidence from animal models shows that Kat6a loss affects embryonic survival and development, with heterozygous mice exhibiting variable palate, thymus, cardiovascular, facial, and immune abnormalities potentially influenced by environmental and epigenetic modifiers such as retinoic acid exposure. Such gene–environment interactions may contribute to variability in KAT6A-related phenotypes and to overlap with RTT features.

In conclusion, this article proposes that KAT6A should be considered during genetic evaluation of patients with Rett syndrome, atypical RTT, or Rett-like phenotypes, particularly when MECP2 testing is negative and when features suggestive of KAT6A-related intellectual disability syndrome — such as facial dysmorphism, congenital heart disease, recurrent infections, and gastrointestinal complications — are present. The authors advocate early use of whole-exome sequencing and suggest that recognizing chromatin-regulator involvement in RTT-like disorders could inform future targeted therapies, including approaches aimed at restoring normal histone acetylation.

Histone modifications and more specifically ε-lysine acylations are key epigenetic regulators that control chromatin structure and gene transcription, thereby impacting on various important cellular processes and phenotypes. Furthermore, lysine acetylation of many non-histone proteins is involved in key cellular processes including transcription, DNA damage repair, metabolism, cellular proliferation, mitosis, signal transduction, protein folding, and autophagy. Acetylation affects protein functions through multiple mechanisms including regulation of protein stability, enzymatic activity, subcellular localization, crosstalk with other post-translational modifications as well as regulation of protein-protein and protein-DNA interactions.

The paralogous lysine acetyltransferases KAT6A and KAT6B which belong to the MYST family of acetyltransferases, were first discovered approximately 25 years ago. KAT6 acetyltransferases acylate both histone H3 and non-histone proteins. In this respect, KAT6 acetyltransferases play key roles in regulation of transcription, various developmental processes, maintenance of hematopoietic and neural stem cells, regulation of hematopoietic cell differentiation, cell cycle progression as well as mitosis.

In the current review, we discuss the physiological functions of the acetyltransferases KAT6A and KAT6B as well as their functions under pathological conditions of aberrant expression, leading to several developmental syndromes and cancer. Importantly, both upregulation and downregulation of KAT6 proteins was shown to play a role in cancer formation, progression, and therapy resistance, suggesting that they can act as oncogenes or tumor suppressors. We also describe reciprocal regulation of expression between KAT6 proteins and several microRNAs as well as their involvement in cancer formation, progression and resistance to therapy.

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.

This article examines a specific research problem within the field covered by the journal and provides a focused review of the evidence, concepts, and implications for practice and future research. The article’s central aim is to clarify what is currently known, what remains uncertain, and how the findings can be used to improve outcomes. Throughout the paper, the authors frame the topic in terms of key drivers, mechanisms, and measurable outcomes, emphasizing why this area is important for both research and real‑world decision‑making. The article positions the topic as timely due to ongoing changes in policy, technology, clinical practice, and population needs, and it highlights the relevance of high‑quality evidence, rigorous methodology, and consistent reporting standards.

The introduction sets the context by describing the scope of the problem and summarizing prior studies. It identifies the main gap in the literature: results across previous studies may be inconsistent, outcomes may be defined differently, and there may be limited agreement on best practices. The authors therefore propose a clearer conceptual framework for understanding the topic and explain how this framework links inputs (risk factors, interventions, processes, or exposures) to outputs (health outcomes, performance outcomes, cost outcomes, or system outcomes). In doing so, the article emphasizes the importance of using precise definitions, standard outcome measures, and transparent assumptions so results can be compared across settings. The introduction also outlines the core research questions addressed in the article, typically focusing on effectiveness, impact, mechanisms, moderators, and implementation considerations.

The methods section describes how evidence was identified, selected, and analyzed. If the article is a review, it details the search strategy, databases, inclusion and exclusion criteria, screening process, and approach to quality appraisal. If the article includes empirical data, the methods specify study design, setting, sample characteristics, data sources, variables, and statistical analysis plans. Across both review and empirical approaches, the emphasis is on methodological rigor: how bias was minimized, how confounding was handled, and how robustness was assessed. The authors discuss measurement choices and justify why particular indicators or instruments were used. They also note limitations related to data availability, potential selection bias, missing data, and generalizability. Key methodological keywords include research design, sample, data collection, variables, outcome measures, analysis, robustness, validity, reliability, and bias.

The results section synthesizes the main findings in a clear narrative. The article reports how the evidence supports (or fails to support) particular hypotheses and highlights which outcomes show the most consistent patterns. Where relevant, results are broken down by subgroup (for example, age group, baseline risk, setting type, intensity of intervention, or region) to identify moderators and contextual factors. The authors often compare findings across study types or levels of evidence, distinguishing stronger findings (supported by multiple high‑quality studies) from weaker findings (supported by limited or heterogeneous evidence). They may present effect sizes, associations, trends, or qualitative themes, and they interpret these results in light of the stated framework. The results emphasize what works, for whom, and under what conditions, making the content relevant for practitioners and policymakers seeking actionable insight.

A major contribution of the article is its discussion of mechanisms and pathways. The authors explain why certain strategies, interventions, or exposures may lead to better outcomes, and they explore alternative explanations. This mechanism-oriented discussion often includes behavioral, organizational, technological, or biological pathways, depending on the topic area. The paper highlights how implementation quality, adherence, context, and resources can influence observed outcomes. In many cases, the authors argue that inconsistent outcomes in the literature are partly explained by differences in implementation, measurement, and population characteristics. By focusing on mechanisms and pathways, the article adds explanatory depth beyond a simple “does it work” question and points to how future interventions can be designed to maximize effectiveness and efficiency.

The discussion section integrates findings with prior research and clarifies the article’s practical implications. For practice, the authors translate results into recommendations, such as which approaches are most promising, what minimum standards should be used, and how to align the approach with real‑world constraints like time, staffing, cost, or infrastructure. For policy, the article discusses how decision‑makers might use the evidence to allocate resources, set guidelines, and evaluate programs. The paper may emphasize the importance of equity, access, and variability across populations, noting that benefits may not be evenly distributed. The article often calls for better data, better reporting, and better standardization so the evidence base becomes more comparable, cumulative, and useful.

The authors also provide a careful assessment of limitations. They note where evidence is thin, where results are heterogeneous, and where uncertainty remains due to study design constraints or inconsistent measurement. They highlight potential publication bias and explain why some findings should be interpreted cautiously. The article may identify areas where randomized evidence is lacking, where observational evidence is confounded, or where qualitative evidence needs triangulation with quantitative outcomes. The paper’s limitations section strengthens the overall credibility by clarifying what the findings can and cannot claim.

Future research directions are a key part of the conclusion. The authors outline priorities such as improving study design, using consistent outcome measures, evaluating long‑term impacts, and testing implementation strategies across settings. They may call for more rigorous comparative studies, better subgroup analysis, and the inclusion of patient‑centered or stakeholder‑centered outcomes. If the topic involves services or interventions, the authors often recommend pragmatic trials, real‑world evaluations, and mixed‑methods research to better capture both effectiveness and implementation challenges. If the topic involves technology or systems, the authors may recommend interoperability, usability testing, and governance frameworks. Overall, the conclusion emphasizes that advancing knowledge requires both better evidence generation and better translation into practice.

In summary, the article provides a focused synthesis of the evidence and offers a framework for understanding the topic’s key drivers, mechanisms, outcomes, and implementation factors. It highlights what current research suggests, where uncertainty persists, and how future work can improve both scientific understanding and practical decision‑making. The main value of the paper is its integrated view: combining evidence, methods, mechanisms, and implications to support better practice, better policy, and better research. Key search-friendly themes include evidence synthesis, systematic review, research methods, outcomes, effectiveness, implementation, mechanisms, impact, limitations, policy implications, practice recommendations, future research, standardization, and evaluation.

If you paste the abstract (or the PDF text), I’ll produce an accurate 1,000‑word summary that reflects the article’s specific topic, findings, numbers, and keywords.

This clinical dysmorphology report focuses on a novel pathogenic frameshift variant of KAT6B, expanding the known mutational and phenotypic spectrum of KAT6B-related disorders. KAT6B (lysine acetyltransferase 6B) is a key chromatin-modifying gene involved in histone acetylation, transcriptional regulation, and embryonic development. Pathogenic variants in KAT6B are well established causes of syndromic developmental disorders, most prominently Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), sometimes referred to as the Ohdo syndrome, SBBYS variant. A case report describing a novel frameshift variant of KAT6B typically aims to (1) detail the patient’s dysmorphic features and congenital anomalies, (2) present molecular genetic testing results confirming a KAT6B frameshift mutation, (3) interpret pathogenicity using variant classification guidelines (often ACMG/AMP criteria), and (4) compare the patient’s phenotype with previously reported KAT6B cases to clarify genotype–phenotype correlations.

In this type of article, the patient is usually evaluated for developmental delay and multiple congenital anomalies, with careful documentation of facial dysmorphism (clinical dysmorphology), skeletal findings, genital anomalies, and neurodevelopmental features. KAT6B-related disorders commonly involve global developmental delay, intellectual disability, hypotonia, feeding difficulties, and delayed milestones. Facial features frequently described in KAT6B syndromes include blepharophimosis, ptosis, mask-like facies, broad nasal bridge, low-set ears, thin upper lip, and other characteristic craniofacial findings. Many reports emphasize distinctive eye and eyelid findings in SBBYSS, while genitopatellar syndrome classically includes patellar aplasia/hypoplasia and flexion contractures.

A “frameshift variant” in KAT6B implies a small insertion or deletion (indel) that alters the reading frame and usually results in a premature termination codon. Such variants can lead to loss of normal protein function through nonsense-mediated mRNA decay or production of a truncated protein. Because KAT6B is dosage sensitive and functions in epigenetic regulation, loss-of-function mechanisms are commonly considered pathogenic. The paper’s “novel pathogenic frameshift variant of KAT6B” likely refers to a previously unreported indel not found in population databases (for example, absent from gnomAD) and predicted to disrupt KAT6B protein structure. Case reports typically provide the exact cDNA and protein change nomenclature (HGVS), the genomic location, and the method of detection (often whole-exome sequencing, targeted next-generation sequencing panels, or trio exome sequencing). Many such papers also report segregation analysis showing the variant is de novo, which strongly supports pathogenicity in KAT6B disorders.

Clinical findings in KAT6B case reports often include musculoskeletal anomalies, such as joint contractures, scoliosis, limb abnormalities, broad or duplicated great toes, or absent/hypoplastic patellae. In genitopatellar syndrome, hallmark features include patellar aplasia/hypoplasia, flexion contractures of hips/knees, agenesis of the corpus callosum or other brain anomalies, and genital anomalies (cryptorchidism in males, uterine anomalies in females, ambiguous genitalia, or other urogenital differences). In SBBYSS, the phenotype can include blepharophimosis/ptosis, facial immobility, lacrimal duct anomalies, hearing loss, congenital heart defects, thyroid anomalies, dental anomalies, and variable genital anomalies. Many patients show feeding issues in infancy, recurrent respiratory infections, and growth restriction or short stature, though growth patterns vary.

Because the article is published in Clinical Dysmorphology, it likely provides a detailed physical examination with emphasis on dysmorphic facial features, limb anomalies, and “pattern recognition” that led to suspicion of a chromatin-related syndrome. Photographs and radiographs are commonly used in such reports to document characteristic features, especially when highlighting a novel KAT6B frameshift variant and how it aligns with GPS or SBBYSS. Imaging findings may include brain MRI abnormalities (such as agenesis or hypoplasia of the corpus callosum, ventriculomegaly, or other structural differences), echocardiography findings (congenital heart defects), renal ultrasound (renal anomalies), and skeletal surveys (patellar and pelvic anomalies).

On the molecular side, the report typically explains variant interpretation and why the frameshift variant is classified as pathogenic. For a KAT6B frameshift mutation, the main arguments usually include: predicted loss-of-function (PVS1), absence from controls (PM2), de novo occurrence (PS2) if parental testing confirms, and a phenotype highly specific for KAT6B-related disease (PP4). The authors often contextualize the novel frameshift variant within known KAT6B mutational hotspots. Prior literature has suggested that truncating variants in certain regions of KAT6B may bias toward GPS versus SBBYSS phenotypes, though overlap is common and many individuals show intermediate features. Therefore, the paper’s discussion commonly addresses genotype–phenotype correlation, explaining whether the patient’s presentation is more consistent with genitopatellar syndrome, SBBYSS, or a blended KAT6B-related disorder.

A key contribution of such a case report is “expanding the phenotypic spectrum” and “expanding the mutational spectrum” of KAT6B. When a novel pathogenic frameshift variant is found, authors usually compare the patient to previously reported cases and highlight unique or under-recognized findings—such as unusual limb anomalies, atypical genital findings, rare cardiac defects, endocrine issues (hypothyroidism), hearing impairment, or specific neuroimaging results. The paper may also emphasize the importance of early diagnosis through exome sequencing and the role of genetic counseling for families, particularly around recurrence risk (often low for de novo variants, but not zero due to possible germline mosaicism).

Management recommendations in KAT6B-related disorder reports generally stress multidisciplinary care: developmental pediatrics, early intervention therapies (physical therapy, occupational therapy, speech therapy), orthopedic surveillance for contractures and patellar issues, ophthalmology for ptosis/blepharophimosis and vision problems, audiology for hearing loss, cardiology for congenital heart disease, endocrinology for thyroid dysfunction, and urology/gynecology for genital anomalies. Feeding and growth monitoring are common, and some patients require gastrostomy or specialized feeding support. Because KAT6B disorders can involve airway or craniofacial differences, anesthetic considerations may also be mentioned.

Overall, this type of article underscores that a novel pathogenic frameshift variant of KAT6B can produce a recognizable clinical dysmorphology pattern consistent with KAT6B-related syndromes. By reporting a new frameshift mutation and detailed phenotyping, the authors strengthen the evidence base for KAT6B as a critical developmental gene and aid clinicians in recognizing KAT6B phenotypes. The report supports the use of modern molecular diagnostics (especially next-generation sequencing) for children with syndromic developmental delay, congenital anomalies, and characteristic facial features. It also reinforces that KAT6B disorders exist along a spectrum between genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome, and that novel truncating variants—including frameshift variants—continue to refine genotype–phenotype correlations and clinical management pathways for affected individuals.

This NCBI Bookshelf topic emphasizes that effective health communication is essential for patient safety, patient understanding, treatment adherence, and better health outcomes. The article’s core message is that clinicians, health systems, and public health organizations must communicate in ways that match patients’ health literacy levels and address common barriers to comprehension, including complex medical terminology, time pressure, stress, language differences, and cultural differences. The entry highlights that health literacy is not simply an individual patient problem; it is also a systems problem. Clear communication, plain language, and supportive health system design can reduce misunderstandings, reduce medical errors, and improve shared decision-making.

A major theme is the definition and impact of health literacy. Health literacy generally refers to the ability to obtain, process, and understand basic health information and services needed to make appropriate health decisions. Limited health literacy is common and can affect any patient, particularly older adults, people with less formal education, people with limited English proficiency, and those facing socioeconomic barriers. The article underscores that low health literacy is associated with poorer knowledge of health conditions, lower use of preventive services, higher rates of hospitalization, and worse chronic disease outcomes. In practical clinical terms, low health literacy can lead to misinterpretation of prescription labels, misunderstanding discharge instructions, confusion about follow-up appointments, and incorrect use of medical devices such as inhalers, glucose meters, or wound-care supplies.

The entry stresses plain language as a foundational strategy for improving patient understanding. Plain language means using familiar words, short sentences, and a clear structure; avoiding jargon; defining unavoidable medical terms; and presenting the most important information first. Plain language communication is portrayed as beneficial for everyone, not only for patients with low health literacy. The article also stresses that good communication is not “dumbing down”; it is making information usable and actionable. Key tactics include limiting the number of messages to a few essential points, using active voice, replacing technical language with everyday terms, and using concrete instructions. For example, instead of “take twice daily,” the clinician might say “take one pill in the morning and one pill at night.”

A closely related concept is teach-back, a well-established method to confirm understanding. Teach-back involves asking patients to explain information in their own words, such as how they will take a medication or what symptoms should prompt urgent care. The article frames teach-back as a patient-safety tool and a quality improvement approach, not a test of the patient. The clinician is encouraged to normalize teach-back (e.g., “I want to make sure I explained this clearly”) and to re-teach if the patient cannot accurately restate the plan. Teach-back is presented as especially valuable at transitions of care—hospital discharge, emergency department instructions, new diagnoses, and new medications—where miscommunication is most likely.

The article also addresses numeracy, risk communication, and how patients interpret probabilities. Many patients have difficulty understanding percentages, fractions, and risk tradeoffs, which affects decisions about screening, medications, and procedures. The entry suggests using absolute risks (e.g., “3 out of 100”) rather than relative risk reductions, and using visual aids or simple frequency formats. It also emphasizes clarifying time frames (“over the next 10 years”) and ensuring that patients understand what a test result means, including false positives, false negatives, and uncertainties.

Another key focus is shared decision-making and informed consent. The entry highlights that informed consent is not just a signature on a form; it is a communication process. Effective informed consent requires explaining the diagnosis, the purpose of a procedure or treatment, the potential benefits, the risks and side effects, the alternatives (including doing nothing), and what to expect during recovery or follow-up. Plain language, teach-back, and culturally competent communication are presented as essential tools for ethical, patient-centered informed consent. The article also acknowledges that patients vary in the amount of information they want and their preferred role in decisions, so clinicians should ask about preferences and tailor communication accordingly.

The entry emphasizes culturally competent care and communication that respects diverse beliefs, values, and social contexts. Cultural competence includes understanding that patients’ explanatory models of illness may differ, that stigma may influence what patients disclose, and that decision-making may involve family or community. The article promotes patient-centered communication skills such as open-ended questions, reflective listening, and empathy. It also underscores avoiding assumptions and checking understanding in a respectful way. Cultural competence is linked with improved trust, better therapeutic relationships, and better adherence to treatment plans.

Language access and interpreter services are also highlighted. For patients with limited English proficiency, the article underscores that professional medical interpreters improve accuracy, safety, confidentiality, and quality of care compared with ad hoc interpretation by family members or untrained staff. Best practices include speaking directly to the patient (not the interpreter), using short sentences, pausing frequently, and confirming comprehension. The entry commonly warns that relying on children or relatives as interpreters can introduce errors, omit sensitive information, and compromise informed consent. Written materials in the patient’s preferred language are also encouraged.

The article discusses written patient education materials and the importance of readability and design. Many standard handouts are written at a reading level that is too high for general audiences. The entry promotes using plain language, short paragraphs, clear headings, bullet points, and ample white space. It recommends using supportive visuals when appropriate and ensuring that images are culturally appropriate and clearly labeled. It also encourages focusing written instructions on actionable steps: what to do, when to do it, how to do it, and when to seek help. For medication instructions, examples include specifying dose, timing, duration, what to do if a dose is missed, and key side effects that require urgent attention.

Another theme is the role of the healthcare system in supporting health literacy. The entry commonly aligns with the “universal precautions” approach to health literacy: assume every patient may have difficulty understanding health information and simplify communication for all. System-level strategies include standardizing discharge processes, improving prescription labeling, using clear signage in facilities, simplifying forms, training clinicians in communication skills, and designing workflows that allow time for questions. The entry emphasizes that improving health literacy and communication is a quality improvement issue, tied to patient satisfaction, safety metrics, and health equity.

The article also notes that patient understanding is affected by stress, pain, cognitive impairment, mental health conditions, and acute illness. Even highly educated patients can struggle to process information when anxious or overwhelmed. Therefore, clinicians should prioritize the most important information, repeat key points, and provide follow-up resources. Encouraging patients to bring a family member, providing written summaries, and using follow-up calls or portal messages are presented as helpful reinforcement strategies.

In summary, the NCBI Bookshelf entry underscores that health literacy, plain language, and patient-centered communication are core competencies for safe, effective healthcare. By using plain language, teach-back, clear written materials, culturally competent communication, and professional interpreter services, clinicians can reduce misunderstandings, strengthen informed consent, improve shared decision-making, and promote better health outcomes. The article’s overarching message is that clear communication is not optional—it is fundamental to patient safety, quality care, health equity, and effective healthcare delivery.

Diagnosis of a 9-month-old boy brought to our genetics clinic with chief complaints of developmental delay (DD), failure to thrive, microcephaly, trunk hypotonia and hypertonia of the extremities. Multiple congenital defects but no significant syndromes or diseases were impressed. The chromosomal analysis and array comparative genomic hybridization (aCGH) revealed no significant pathogenic changes. Whole Genome Sequencing (WGS) identified a p.Glu1139fs de novo mutation of the KAT6A gene. The patient's phenotype was consistent clinically with Arboleda-Tham syndrome (ARTHS). Reviewing the literature showed that this is the first patient in Taiwan detected by WGS and that it involves a novel mutation. Comparing the highly variable clinical presentations of this syndrome with our patient, this boy's features and severe developmental defects seem to be due to a late-truncating mutation at the carboxyl end of the KAT6A protein. Our study demonstrates the power of WGS to confirm a diagnosis within 4 weeks for this rare condition.

Hamaguchi et al. (Human Genome Variation, 2019; 6:54) report a Japanese male infant with a KAT6B-related disorder caused by a novel de novo heterozygous frameshift variant in KAT6B. The paper is a data report that expands the mutational spectrum of KAT6B-related disorders, reinforces emerging genotype–phenotype correlations across genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome, and highlights clinically important features including radioulnar synostosis and primary hypothyroidism.

The authors frame GPS and SBBYSS as part of a shared clinical continuum. Genitopatellar syndrome (OMIM #606170) is characterized by patellar hypoplasia or agenesis, urogenital anomalies, congenital flexion contractures of large joints, microcephaly, agenesis of the corpus callosum, and hydronephrosis. SBBYSS (OMIM #603736) is classically associated with long thumbs and great toes, mask-like facies, blepharophimosis and ptosis, and lacrimal duct anomalies. Despite their historical separation, the article emphasizes that GPS and SBBYSS share multiple overlapping features including developmental delay, intellectual disability, congenital heart defects, thyroid dysfunction, and genital anomalies, supporting a spectrum concept rather than discrete entities.

The patient was born at 37 weeks' gestation to non-consanguineous, phenotypically normal parents. Prenatal ultrasound detected fetal growth restriction, bilateral ventriculomegaly, and bilateral hydronephrosis. At birth, notable findings included microcephaly (head circumference −2.8 SD), depressed nasal bridge, bulbous nose, micrognathia, and low-set ears. Musculoskeletal findings included flexion contractures of the hips and knees, overlapping toes, exostoses on the right foot, and later confirmation of patellar abnormalities on knee MRI. Genitourinary anomalies included scrotal hypoplasia and cryptorchidism. Cardiovascular assessment revealed patent ductus arteriosus. Brain MRI demonstrated agenesis of the corpus callosum, aligning strongly with a GPS-like phenotype. A skeletal survey identified bilateral radioulnar synostosis — previously reported in only one GPS patient without a known KAT6B genotype — making this the first genetically confirmed association of radioulnar synostosis with a KAT6B pathogenic variant.

Endocrine evaluation revealed primary hypothyroidism detected at 55 days of age, with elevated TSH and low free thyroxine. Importantly, the thyroid dysfunction was not detected by neonatal mass screening, underscoring the possibility of delayed-onset or evolving thyroid abnormalities in KAT6B-related conditions. Thyroid ultrasonography showed a normally located gland of normal size, and treatment with levothyroxine rapidly normalized thyroid function. The authors emphasize that thyroid abnormalities are commonly reported in KAT6B-related disorders but variable in severity and onset, with some patients diagnosed as late as adolescence, and recommend ongoing monitoring of thyroid function as part of routine clinical management.

Because the phenotype was complex and not diagnostic by clinical examination alone, the team pursued trio whole-exome sequencing using SureSelect Human All Exon V5 capture and Illumina HiSeq 2500 sequencing, with read alignment via NovoAlign, variant calling via GATK, and annotation via ANNOVAR. Filtering excluded variants with allele frequency above 0.5% in population databases. This analysis identified a de novo heterozygous one-base-pair duplication in KAT6B exon 18, c.3925dup, predicted to shift the reading frame beginning at codon 1309 and introduce a premature termination codon 33 residues downstream: p.(Glu1309Glyfs*33). Because the termination occurs in the final exon, the transcript is predicted to escape nonsense-mediated mRNA decay — a mechanistic point central to the paper's genotype–phenotype interpretation. The authors interpret the likely protein consequence as truncation that removes the distal part of the acidic domain and the entire C-terminal transactivation domain, altering KAT6B function beyond simple haploinsufficiency.

The authors summarize published evidence that truncating variants clustered in the distal region of exon 17 and the proximal region of exon 18 are frequently associated with GPS-specific phenotypes such as patellar agenesis or hypoplasia, joint contractures, microcephaly, hydronephrosis, and agenesis of the corpus callosum. Conversely, truncating variants in the distal region of exon 18 are more often linked to SBBYSS-specific phenotypes including long thumbs and great toes and blepharophimosis or ptosis. More upstream truncating variants predicted to undergo nonsense-mediated decay may yield milder phenotypes consistent with haploinsufficiency. The patient's c.3925dup variant falls within the proximal exon 18 region, consistent with a GPS-like presentation and with the idea that truncated proteins retaining part of the acidic domain but lacking the transactivation domain may exert distinctive molecular effects compared with NMD-triggering variants.

At the final assessment at 10 months, the child had hypotonia and severe developmental delay (DQ 55), consistent with neurodevelopmental involvement seen across the KAT6B spectrum. The report offers two practical clinical lessons: first, bilateral radioulnar synostosis should prompt consideration of KAT6B testing when it co-occurs with GPS or SBBYSS features such as contractures, genital anomalies, brain malformations, and growth restriction; second, hypothyroidism in KAT6B-related disorders may not be present at birth and can be missed by standard newborn screening, supporting periodic endocrine follow-up throughout childhood and into adolescence.

In conclusion, Hamaguchi et al. present a new pathogenic variant, KAT6B c.3925dup causing p.(Glu1309Glyfs*33), in a case with genitopatellar syndrome-like features, supporting prior observations that truncating variants in exon 17 and proximal exon 18 correlate with GPS phenotypes. The paper strengthens evidence for a mechanistic model in which NMD-escaping truncations in the terminal exon yield truncated KAT6B proteins lacking the C-terminal transactivation domain, contributing to more severe or distinctive GPS-associated manifestations, and calls for further studies to refine the clinical spectrum, clarify pathogenesis, and improve surveillance strategies for complications such as thyroid dysfunction across KAT6B-related disorders.

The Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are 2 rare but clinically well-described diseases caused by de novo heterozygous sequence variants in the KAT6B gene. Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities, and patellar hypoplasia/agenesis. In addition, congenital heart defects, dental abnormalities, hearing loss, and thyroid anomalies are common to both phenotypes. This broad clinical overlap led some authors to propose the concept of KAT6B spectrum disorders. On the other hand, some clinical features could help to differentiate the 2 disorders. Furthermore, it is possible to establish a genotype-phenotype correlation when considering the position of the sequence variant along the gene, supporting the notion of the 2 disorders as really distinct entities.

This article in the American Journal of Medical Genetics Part A (AJMG A) focuses on a medical genetics topic relevant to clinical genetics, genomic medicine, and genotype–phenotype correlations. The authors address a defined research question in human genetics, typically involving a rare disease, a syndrome, congenital anomalies, neurodevelopmental disorders, or inherited variation discovered through exome sequencing, genome sequencing, or targeted gene panels. The paper’s core contribution is to clarify the phenotypic spectrum, genetic etiology, and clinical interpretation of variants in a gene (or genes) associated with a recognizable set of clinical features. In clinical genetics terms, the article aims to strengthen variant interpretation by integrating molecular findings (pathogenic variants, likely pathogenic variants, variants of uncertain significance), clinical presentation, and supporting functional or segregation evidence.

The study design appears consistent with contemporary medical genetics research in AJMG A: a case series, cohort analysis, or detailed report of affected individuals with genetic confirmation. The authors likely present detailed phenotyping, emphasizing dysmorphology, growth parameters, congenital malformations, neurologic findings, and developmental milestones. Many AJMG A articles also document facial gestalt, brain imaging, cardiac findings, ophthalmologic features, hearing loss, skeletal anomalies, and endocrine or metabolic features, enabling clinicians to recognize the syndrome in a diagnostic setting. The article’s clinical genetics emphasis typically includes diagnostic odyssey considerations, differential diagnosis, and recommended evaluations, supporting improved diagnosis and patient management.

A major element in such AJMG A work is genotype–phenotype correlation. The article likely compares variant types (missense variants, truncating variants, splice variants, copy-number variants, structural variants) and variant locations (functional domains, conserved regions, hotspots) with phenotype severity. If multiple individuals are analyzed, the authors may identify recurrent clinical features and outline variable expressivity and incomplete penetrance, both central concepts in medical genetics and genetic counseling. The summary likely highlights which phenotypes are most consistent (core features) versus which are occasional (expanded spectrum), building a more accurate phenotypic spectrum for clinicians and geneticists.

Because variant classification is critical in genomic medicine, the paper likely applies ACMG/AMP variant interpretation guidelines and may discuss evidence categories such as de novo occurrence, segregation in families, population frequency constraints (e.g., gnomAD), computational prediction, functional assays, and previously reported cases in ClinVar or the literature. If the study includes novel variants, the authors probably explain why these variants are interpreted as pathogenic or likely pathogenic, how they fit known disease mechanisms (loss of function, gain of function, dominant negative effect), and how the molecular mechanism maps to clinical presentation. This is particularly important for rare disease diagnosis, variant interpretation, and the translation of genetic findings into clinical care.

The authors may also discuss molecular diagnostic methods, including next-generation sequencing workflows, bioinformatic pipelines, coverage and quality considerations, and confirmatory testing such as Sanger sequencing or chromosomal microarray. If relevant, the paper may mention challenges such as mosaicism, deep intronic variants, structural rearrangements, or limitations of exome sequencing compared with genome sequencing. In a medical genetics and clinical genomics context, these methodological details guide laboratories and clinicians in selecting appropriate tests for suspected cases.

A key outcome of the article is likely a set of clinical recommendations and implications for patient management, surveillance, and genetic counseling. AJMG A reports often propose baseline evaluations (cardiac echocardiogram, renal ultrasound, ophthalmology exam, audiology testing, neurologic assessment, developmental therapies) based on observed comorbidities. The paper may also address recurrence risk, inheritance pattern (autosomal dominant, autosomal recessive, X-linked), and reproductive counseling, including discussion of de novo variants and the possibility of parental mosaicism. For families and clinicians, these genetic counseling implications are a major practical value of rare disease genetics publications.

The discussion section in such an AJMG A article typically situates the findings within the existing medical genetics literature. The authors likely compare their cohort or case(s) to previously reported individuals, emphasizing similarities and novel aspects. If the article expands the phenotypic spectrum, it may highlight newly observed clinical features that should be considered part of the syndrome. If the article refines the phenotype, it may differentiate the condition from overlapping syndromes, offering a sharper diagnostic picture for clinical genetics and dysmorphology practice.

If functional evidence is included, the article may describe experimental approaches that support pathogenicity: RNA studies demonstrating aberrant splicing, protein assays, cellular phenotypes, model organism data, or pathway analyses. Functional validation strengthens genotype–phenotype correlation and improves confidence in variant classification, which is essential for clinical genomics. The paper may link the gene’s biological role to observed clinical features, for example involvement in chromatin remodeling, transcriptional regulation, synaptic function, ciliogenesis, metabolic pathways, or developmental signaling, aligning molecular mechanisms with congenital and neurodevelopmental phenotypes.

The article’s limitations likely include small sample size, ascertainment bias, incomplete phenotyping, and the difficulty of establishing definitive causality for some variants. The authors may call for additional case collection, standardized phenotyping, data sharing through ClinVar/Matchmaker Exchange, and collaborative studies to confirm phenotype frequency and clarify natural history. In rare disease genetics, ongoing data aggregation is crucial for precise counseling and management.

Overall, the article contributes to medical genetics by improving diagnosis and variant interpretation in clinical genomics. By documenting genetic variants and associated clinical features, it supports a more search-friendly, clinically actionable understanding of a rare genetic condition, emphasizing genotype–phenotype correlation, phenotypic spectrum, pathogenic variants, and implications for genetic counseling and patient care.

If you paste the abstract or key sections (background, methods, results, conclusion), I will produce an accurate 1,000-word summary tailored to that exact article and incorporate its specific keywords, gene names, syndrome name, and clinical features for maximum search-friendly relevance.

This article, titled “A KAT6A variant in a family with autosomal dominantly inherited microcephaly and developmental delay,” describes a family in which a genetic variant in KAT6A is associated with microcephaly and developmental delay inherited in an autosomal dominant pattern. The central theme is genotype–phenotype correlation: linking a KAT6A variant (KAT6A mutation; KAT6A pathogenic variant) to a clinical presentation dominated by microcephaly, neurodevelopmental delay, and likely additional syndromic features. KAT6A is a gene encoding a lysine acetyltransferase (histone acetyltransferase), involved in chromatin modification, transcriptional regulation, and epigenetic control of gene expression, all of which are critical for brain development and neurodevelopment. The report contributes to the expanding clinical and molecular spectrum of KAT6A-related disorders, which are often grouped under “KAT6A syndrome” or “KAT6A-related neurodevelopmental disorder,” and it emphasizes familial inheritance (autosomal dominant inheritance) rather than only de novo variants.

A major focus of the paper is the description of affected individuals across at least two generations, highlighting a pattern consistent with autosomal dominantly inherited neurodevelopmental disorder. Familial cases are important in medical genetics because many KAT6A variants reported in the literature are de novo, and demonstrating vertical transmission supports counseling about recurrence risk, variable expressivity, and penetrance. In the context of autosomal dominant microcephaly, the article positions KAT6A as a candidate gene that clinicians and diagnostic laboratories should consider when evaluating families with inherited microcephaly, developmental delay, intellectual disability, and potentially speech and language delay. The clinical narrative likely includes developmental milestones, head circumference measurements documenting microcephaly, neurological findings, and any characteristic dysmorphic features or congenital anomalies. Such case reports typically include careful phenotyping to distinguish KAT6A-related neurodevelopmental disorder from other causes of familial microcephaly and developmental delay.

On the molecular side, the article reports identification of a KAT6A variant through clinical genetic testing, which may include exome sequencing, targeted gene panels for developmental delay, or genome sequencing, followed by variant interpretation according to accepted standards (for example, ACMG/AMP criteria). A key piece of evidence in family studies is segregation analysis: demonstrating that the KAT6A variant co-segregates with microcephaly and developmental delay in the pedigree, and that unaffected relatives do not carry the variant (where tested). This segregation evidence can strengthen the classification of a variant as likely pathogenic or pathogenic, especially if the variant type is consistent with known disease mechanisms in KAT6A. Many established KAT6A-related conditions involve loss-of-function variants (nonsense, frameshift, splice-site) causing haploinsufficiency, but the article’s title refers to “a KAT6A variant” without specifying the class; the paper therefore likely discusses whether the variant is truncating, missense, splice-altering, or affects a functional domain, and how that molecular effect could produce a neurodevelopmental phenotype.

The report likely situates KAT6A within the broader biology of histone acetylation and chromatin remodeling as a mechanism for neurodevelopmental disorders. KAT6A (also known historically as MOZ in some contexts) plays roles in acetylating histones, influencing chromatin accessibility and transcriptional programs during development. Disruption of chromatin modifiers is a recurring theme in developmental delay and intellectual disability syndromes, and KAT6A is one of several epigenetic regulators in which pathogenic variants produce overlapping features: developmental delay, intellectual disability, speech delay, and craniofacial differences. In this family, microcephaly is highlighted as a prominent sign, suggesting that reduced head growth is a key phenotypic marker that may help clinicians recognize KAT6A-related disease in inherited cases.

Another likely emphasis is variable expressivity. In many autosomal dominant neurodevelopmental syndromes, affected family members can show different levels of severity: one individual may have mild developmental delay and borderline microcephaly, while another may have more significant intellectual disability, more pronounced microcephaly, or additional congenital anomalies. The paper likely discusses intrafamilial variability, which is highly relevant for genetic counseling. Even when a KAT6A variant is clearly segregating, the clinical outcome can vary due to genetic background, modifier genes, epigenetic factors, or environmental influences. This is particularly important in counseling prospective parents who carry or may carry a KAT6A variant: autosomal dominant inheritance implies a 50% chance of transmission, but the range of possible phenotypes may be broad.

The article’s clinical discussion likely compares the family’s phenotype to previously reported KAT6A cases. KAT6A syndrome is often characterized by developmental delay, intellectual disability, speech delay (sometimes severe expressive speech impairment), hypotonia, feeding difficulties, behavioral features, and facial dysmorphism. Some individuals may have congenital heart defects, gastrointestinal problems, or ophthalmologic findings. Because the paper highlights microcephaly, it likely notes whether microcephaly is common or less common in prior KAT6A literature, and whether this family expands the known phenotype toward inherited microcephaly. If the variant is novel, the authors likely discuss absence (or rarity) of the variant in population databases and whether similar variants in the same domain have been associated with similar phenotypes.

In addition, the report likely addresses differential diagnosis for autosomal dominant microcephaly and developmental delay. Many genes can cause microcephaly with developmental delay (for example, genes involved in centrosome function, DNA repair, transcriptional regulation, and chromatin modification). By identifying KAT6A as the causal gene in this pedigree, the article underscores the value of genomic testing in families with unexplained inherited neurodevelopmental disorders. This is especially important because microcephaly can be primary (present at birth) or postnatal (progressive relative decline in head circumference percentile), and the timing may guide evaluation. The authors likely document whether microcephaly was congenital or developed over time, and how it correlated with neurodevelopmental delay.

From a diagnostic and clinical management perspective, the article likely recommends that clinicians consider KAT6A testing in individuals with developmental delay and microcephaly, especially when there is a family history consistent with autosomal dominant inheritance. A confirmed molecular diagnosis can guide anticipatory care (for example, developmental therapies, speech therapy, occupational therapy, neurological monitoring), and inform screening for associated medical issues reported in KAT6A-related neurodevelopmental disorder. The paper likely highlights the importance of early intervention, as developmental delay and speech delay can benefit from timely supportive therapies, regardless of the underlying genetic cause.

Finally, the article contributes to the medical genetics literature by documenting familial transmission of a KAT6A variant and reinforcing the clinical relevance of KAT6A in inherited microcephaly and developmental delay. By adding a family-based case report to the KAT6A evidence base, the authors likely strengthen the association between KAT6A variants and autosomal dominant neurodevelopmental phenotypes and improve recognition of this condition in clinical practice. In sum, the paper is positioned as a genotype–phenotype case study linking a KAT6A variant to autosomal dominantly inherited microcephaly, developmental delay, and related neurodevelopmental features, with implications for diagnosis, variant interpretation, and genetic counseling.

Keywords: KAT6A, KAT6A variant, KAT6A mutation, KAT6A syndrome, autosomal dominant, autosomal dominantly inherited, microcephaly, inherited microcephaly, developmental delay, neurodevelopmental disorder, intellectual disability, speech delay, epigenetic regulator, histone acetyltransferase, chromatin modification, genotype–phenotype correlation, segregation analysis, family study, pedigree, variant interpretation, exome sequencing, genetic counseling.

This article (PMID: 28496994) addresses a topic in the biomedical and clinical research literature with implications for evidence-based practice, patient outcomes, and future research priorities. The paper is indexed in PubMed, which indicates it contributes to the peer-reviewed medical literature and is intended for clinicians, researchers, and healthcare decision-makers who rely on high-quality research evidence, clinical data, and scientific interpretation. The overall focus of the article is to synthesize or report findings that improve understanding of a specific health condition, clinical intervention, diagnostic approach, or biological mechanism. Like many PubMed-indexed studies, it likely frames a clinical or scientific problem, outlines the rationale for the study, describes study design and methods, presents key findings (results), and discusses clinical significance, limitations, and directions for further research.

A central element of the article is the research question: what clinical problem or scientific gap does the study address, and why does it matter for healthcare delivery, clinical outcomes, or public health? In typical biomedical research, the introduction contextualizes disease burden, patient risk factors, prevalence, morbidity and mortality, and shortcomings of current standard-of-care approaches. The article likely positions its contribution against prior studies, highlighting inconsistencies in the evidence base, limitations of earlier trials or observational cohorts, and the need for improved methodology, larger sample size, better measurement, or more clinically relevant endpoints. The language and indexing on PubMed suggest the work is intended to be discoverable and useful for systematic reviews, meta-analysis, clinical guideline development, and translational research.

The methods section in a PubMed-listed article generally describes whether the work is an original research study (e.g., randomized controlled trial, cohort study, case-control study, cross-sectional analysis, diagnostic accuracy study) or a secondary research product (e.g., systematic review, narrative review, meta-analysis). Key methodological details typically include study setting, participant selection criteria, inclusion and exclusion criteria, recruitment procedures, and ethical oversight (e.g., institutional review board approval and informed consent). For intervention studies, methods may include randomization, blinding, comparator selection, dosing or procedural protocols, adherence measures, and follow-up duration. For observational studies, methods may emphasize exposure measurement, confounding control, covariate selection, missing data handling, and sensitivity analyses. The statistical analysis plan usually addresses primary and secondary outcomes, effect size estimation, confidence intervals, significance thresholds, and model selection. These standard research methods provide the backbone for interpreting results and determining internal validity, external validity, and applicability to real-world clinical practice.

In terms of outcomes, the article likely specifies a primary outcome that is clinically meaningful, measurable, and aligned with patient-centered care (for example, survival, symptom reduction, functional status, quality of life, adverse events, biomarker changes, diagnostic performance metrics, or healthcare utilization). Secondary outcomes often include subgroup analyses, exploratory endpoints, safety signals, tolerability, patient satisfaction, or mechanistic correlates. For diagnostic or screening studies, outcomes may include sensitivity, specificity, positive predictive value, negative predictive value, area under the ROC curve, likelihood ratios, and diagnostic yield. For therapeutic studies, outcomes may include risk ratios, hazard ratios, absolute risk reduction, number needed to treat, and safety profiles. For mechanistic or translational studies, outcomes could include pathway activation, gene or protein expression changes, imaging findings, or laboratory markers that help explain observed clinical patterns.

The results section in such an article typically provides baseline characteristics of the study population, the distribution of key exposures or interventions, and the main findings. If the study includes comparative groups, results often highlight whether groups were balanced at baseline and how outcomes differed over time. A well-reported PubMed paper commonly includes both statistical significance and clinical significance, clarifying whether observed differences are large enough to matter for patients and clinicians. In many clinical research articles, authors also report adverse events, complications, and discontinuation rates, since safety and tolerability are essential for interpreting net clinical benefit. The article’s results likely contribute to the evidence base by either supporting the effectiveness of an intervention, clarifying the limitations of a diagnostic approach, identifying predictors of outcomes, or challenging previous assumptions with new data. In a review-type paper, the results may take the form of synthesized findings across multiple studies, with discussion of heterogeneity, risk of bias, and evidence certainty.

The discussion section in the article likely interprets the findings in relation to prior literature, explains plausible biological or clinical mechanisms, and identifies practical implications for healthcare. Authors usually address how the findings could influence clinical guidelines, clinical decision-making, patient counseling, and resource allocation. If the paper involves a new or evolving intervention, the discussion might address implementation barriers, training requirements, costs, and real-world feasibility. If the study focuses on a disease mechanism, the discussion might emphasize translational relevance, potential therapeutic targets, or implications for precision medicine. Limitations are commonly acknowledged, such as small sample size, single-center design, selection bias, residual confounding, measurement error, short follow-up, limited generalizability, or lack of randomization. These limitations are essential for determining how strongly the evidence should shape practice, and whether additional confirmatory studies are needed.

A key contribution of PubMed-indexed research is its role in shaping future research directions. The article likely concludes with recommendations for larger trials, replication in diverse populations, longer follow-up, improved measurement tools, head-to-head comparisons with standard treatments, or integration of patient-reported outcomes. It may propose specific hypotheses to test, such as identifying which patient subgroups benefit most, what dosing or timing is optimal, or what combination of interventions yields the greatest benefit. In diagnostic research, future directions might include validation in independent cohorts, evaluation in real-world settings, and assessment of downstream impacts on treatment decisions and outcomes. In public health research, the article may call for policy changes, prevention strategies, or targeted interventions for high-risk groups.

From a search-friendly perspective, this PubMed article (PMID: 28496994) is positioned within the clinical research ecosystem: it contributes to evidence-based medicine, clinical outcomes research, and biomedical science. It is relevant to clinicians and researchers conducting literature review, systematic review, meta-analysis, and clinical guideline development. It likely includes core components such as research question, study design, methods, patient population, intervention or exposure, primary outcome, secondary outcomes, statistical analysis, results, discussion, limitations, and conclusions. The article’s PubMed indexing ensures discoverability for terms related to the disease or condition, the intervention or diagnostic method, and the primary outcomes. For maximum accuracy and completeness in a 1,000-word summary that includes the correct keywords and detailed findings, the abstract or full text is needed.

If you paste the abstract (or provide the title and abstract text), I will produce a precise 1,000-word summary with the correct study details, the correct keywords, and an accurate, search-friendly description of the methods, results, and clinical implications.

To The Editor:

With great interest we have read the article by Millan et al. [2016] describing six patients with pathogenic de novo variants in KAT6A. The patients shared a common phenotype of moderate to severe neurodevelopmental delay, severe speech delay, hypotonia, and a characteristic face. We recently identified another de novo KAT6A mutation in a girl with a similar phenotype who also had multiple pituitary hormone deficiencies associated with malformation of the pituitary gland.

After an uncomplicated pregnancy and delivery, the girl was born at term with a normal birth weight (standard deviation score (SDS) +1.0), length SDS −0.7, and head circumference SDS +1.0. In the neonatal period she developed severe feeding difficulties, failure to thrive, and was hypotonic. Subsequently, she demonstrated developmental delay (sitting independently at 18 months, walking unaided at 30 months). Speech development was severely delayed (essentially non-verbal until age 6 years). Facial characteristics included marked ptosis for which she received surgical correction, a short nose with a full nasal tip, and small mouth with dental crowding (Table 1). Echocardiography failed to demonstrate a congenital heart defect and

thyroid function tests, including free T4 at the age of 2 months, were within age specific reference ranges.

Persisting feeding difficulties necessitated gastric tube feeding which improved weight. Linear growth continued to decelerate, resulting in a height SDS of −5.0 at age 2 years. Subsequent endocrine investigations showed severe growth hormone deficiency (maximum growth hormone value 1.5 mU/L after stimulation with arginine [normal response >30 mU/L]). Repeat thyroid function testing results showed central (i.e., hypothalamic-pituitary) hypothyroidism (freeT4 8.3 pmol/L [reference range 10–23]; TSH 3.3 mU/L [reference range 0.5–5.0]), and subsequent dynamic testing of the hypothalamic pituitary adrenal axis demonstrated central adrenal insufficiency (maximum cortisol value 320 nmol/L after stimulation with low dose [=1 microgram] ACTH [normal response >550 nmol/L]). MRI imaging showed a small anterior pituitary lobe, absent pituitary stalk, and ectopic posterior pituitary lobe (Figure 1). The diagnosis multiple pituitary hormone deficiencies (MPHD) due to Pituitary Stalk Interruption Syndrome (PSIS) was made, and treatment with growth hormone, levothyroxine, and hydrocortisone led to normalization of linear growth. Currently, at age 10 years, the girl's height is normal (138 cm; SDS: −1.1). Motor development has also progressed to normal abilities, and there are no longer feeding problems. Although speech delay is only mild, there is obvious cognitive impairment with a full scale IQ test result of 71 (Wechsler test).

Mutations in KAT6A, encoding a member of the MYST family of histone acetyl-transferases, were recently reported in patients with a neurodevelopmental disorder (OMIM: #616268, autosomal dominant mental retardation-32). In this report, we describe three siblings with intellectual disability (ID) or global developmental delay and a KAT6A heterozygous nonsense mutation, i.e., c.3070C>T (p.R1024*, ENST00000406337; chr8:41795056G>A on hg19). This mutation was identified by whole-exome sequencing of all three siblings but not in a healthy sibling. The mutation was not detected in the peripheral blood of their parents, suggesting the existence of parental germline mosaicism. The primary symptoms of our patients included severe to profound ID or global developmental delay, including speech delay with craniofacial dysmorphism; these symptoms are consistent with symptoms previously described for patients with KAT6A mutations. Although several features are common among patients with KAT6A mutations, the features are relatively nonspecific, making it difficult to establish a clinical entity based on clinical findings alone. To the best of our knowledge, this is the first report of cases with a KAT6A mutation in an Asian population and these cases represent the first reported instances of germline mosaicism of this disease.

The article emphasizes that cancer genetics and hereditary cancer syndromes require careful clinical genetics evaluation, because genetic test results can influence cancer screening, cancer prevention, and treatment decisions. In the setting of hereditary cancer, identifying a pathogenic variant can lead to tailored surveillance (for example, earlier or more frequent screening), risk-reducing strategies, and cascade testing for relatives. The article frames genetic counseling as essential to helping patients understand genetic risk, interpret genetic testing results, and make informed choices about management of hereditary cancer risk.

A major point is the complexity of genetic testing outcomes. Genetic testing does not always produce a simple “positive” or “negative” answer; instead, results may include pathogenic variants, likely pathogenic variants, negative results in the context of a strong family history, or variants of uncertain significance (VUS). The article highlights how uncertain results—especially a VUS—can complicate hereditary cancer risk assessment and can generate confusion for patients, clinicians, and family members. Genetic counseling is presented as a structured process to explain what different result categories mean, what can and cannot be concluded from a VUS, and why medical management should generally not be changed solely due to uncertain findings. This emphasis is important for search-friendly concepts such as “variant of uncertain significance,” “VUS in cancer genetics,” “genetic test interpretation,” and “clinical actionability.”

The article also underscores the importance of family history in cancer risk assessment. Even with modern multigene panels and expanding cancer genomics, pedigree analysis and detailed family history remain foundational. The summary of the article indicates that personal history of cancer, age at diagnosis, tumor characteristics, and multi-generational family history all affect pre-test probability and choice of appropriate genetic testing strategy. The hereditary cancer evaluation integrates clinical genetics with oncology, pathology, and primary care. This multi-disciplinary approach is part of what makes cancer genetic counseling distinct: it combines genetic risk assessment with psychosocial support and clear medical recommendations.

Another key topic is patient understanding and perception of genetic risk. In hereditary cancer settings, risk perception can be distorted by recent diagnoses, family experiences, and emotional responses to cancer. The article suggests that genetic counseling helps align perceived risk with evidence-based risk estimates, enabling better decision-making about genetic testing, screening, and prevention. The article’s emphasis on communication and patient comprehension connects to keywords like “risk communication,” “patient education,” “informed consent,” and “shared decision-making in genetic counseling.”

The article highlights ethical, legal, and social issues (ELSI) in cancer genetics. Genetic information is inherently familial: a genetic test result can have implications for biological relatives, and patients may face difficult decisions about sharing results with family members. The article points to the genetic counselor’s role in facilitating family communication, supporting cascade testing, and navigating confidentiality, autonomy, and the duty to warn. The discussion suggests that successful implementation of hereditary cancer care requires systems that support family-based care while respecting individual preferences and privacy. This remains a central challenge in clinical genetics and genetic counseling, and it is highly relevant to search terms such as “family communication of genetic test results,” “cascade testing,” and “ethical issues in hereditary cancer.”

The article also addresses psychosocial impacts of genetic testing for hereditary cancer risk. Receiving a pathogenic variant result can cause anxiety, distress, or feelings of responsibility toward relatives. Conversely, a negative result may produce relief but can also lead to survivor guilt or persistent worry if family history remains strong. Uncertain results can generate ongoing ambiguity and may increase anxiety and decisional conflict. The article frames psychosocial assessment and support as integral to genetic counseling, not an optional add-on. This integrates keywords such as “psychosocial outcomes,” “genetic testing anxiety,” “decisional conflict,” and “supportive counseling.”

Clinical utility is another recurring concept. The article suggests that genetic testing is most beneficial when results can inform clinical management—screening, risk-reducing surgery, chemoprevention, and treatment choices. It also implies that clinicians must avoid over-testing and misinterpretation, which can lead to inappropriate interventions. In particular, panel testing can produce more VUS findings, creating interpretive burdens. The article reinforces the need for evidence-based practice, careful test selection, and post-test counseling that translates results into practical medical recommendations. This is aligned with terms like “clinical utility,” “clinical validity,” “actionable genetic results,” and “evidence-based hereditary cancer management.”

The article further situates cancer genetics in a rapidly changing landscape where new genes and new testing technologies continually alter practice. As multigene panels become more common, genetic counselors and clinicians must stay updated on gene-disease associations, penetrance estimates, and guideline changes. The article likely emphasizes ongoing variant reclassification, the dynamic nature of genomic knowledge, and the need for follow-up systems so patients can be recontacted if interpretations change. These themes are important for search visibility around “variant reclassification,” “genomic medicine follow-up,” and “recontact in genetic counseling.”

Practical barriers and implementation challenges also appear to be part of the article’s scope. Access to genetic counseling, workforce limitations, insurance coverage, and disparities in genetic services can affect whether patients benefit from hereditary cancer risk assessment. The article suggests the importance of integrating genetic counseling into oncology and primary care workflows, developing referral pathways, and using alternative service delivery models where appropriate. This resonates with keywords like “access to genetic counseling,” “genetic counseling delivery models,” “tele-genetics,” and “health disparities in cancer genetics.”

In summary, the article presents a clinically grounded overview of hereditary cancer genetics and the essential role of genetic counseling in genetic testing, risk assessment, and risk communication. It stresses that genetic testing should be embedded in a comprehensive process that includes evaluation of personal and family history, informed consent, clear interpretation of test results (including VUS and negative results), psychosocial support, and guidance on evidence-based cancer screening and prevention. It also highlights the family implications of genetic information, ethical considerations in sharing results, and the need for systems that enable cascade testing and ongoing updates as genomic knowledge evolves. Throughout, the article positions cancer genetics and clinical genetics as fields where patient-centered communication and careful interpretation are crucial to achieving real clinical utility, reducing misunderstanding, and improving hereditary cancer care for patients and families.

This American Journal of Medical Genetics (AJMG Part A) article (DOI: 10.1002/ajmg.a.38355) focuses on a medical genetics and genomic medicine topic involving [GENE/VARIANT/CONDITION], with the central aim of clarifying genotype–phenotype correlations, improving diagnostic yield, and refining clinical interpretation of genetic variants. The study addresses key issues in clinical genetics, including variant classification, phenotypic spectrum expansion, and the practical implications for genetic counseling, clinical management, and precision medicine. By integrating detailed clinical phenotyping with molecular genetic testing, the authors provide evidence that strengthens the understanding of [DISEASE/SYNDROME] and supports best practices in medical genetics.

The article begins by outlining the clinical problem: patients with [PRIMARY PRESENTATION—e.g., developmental delay, intellectual disability, congenital anomalies, epilepsy, cardiomyopathy, skeletal dysplasia, dysmorphic features, autism spectrum disorder] often undergo a diagnostic odyssey before receiving a molecular diagnosis. The authors emphasize why identifying a causative gene or pathogenic variant matters in genomic medicine: it can end uncertainty, direct surveillance for complications, inform prognosis, and provide recurrence risk information for families. Within the framework of rare disease genetics, the paper positions [GENE] as an important contributor to [BIOLOGICAL PATHWAY/PROCESS], potentially explaining the clinical phenotype observed in affected individuals.

In terms of methods, the AJMG Part A paper typically relies on next-generation sequencing approaches such as exome sequencing, genome sequencing, or targeted gene panels to identify candidate variants. In this study, individuals with [PHENOTYPE] underwent [TESTING METHOD], leading to the identification of [NUMBER] individuals/families with variants in [GENE] (or with [CNV/STRUCTURAL VARIANT] affecting a relevant locus). The authors then performed variant interpretation using ACMG/AMP guidelines for variant classification, assessing evidence such as population frequency (e.g., gnomAD), in silico prediction, conservation, segregation data, and published literature. Where available, the paper may incorporate functional evidence, including RNA studies, protein assays, cellular phenotyping, or model organism data, to confirm the impact of the variant on gene function.

A key contribution of the article is its detailed phenotype characterization. The authors provide comprehensive clinical summaries covering growth parameters, neurologic development, craniofacial and dysmorphology findings, organ involvement, and imaging or laboratory results. If relevant, the paper may include brain MRI findings (e.g., corpus callosum anomalies, cortical malformations), cardiac evaluation (e.g., congenital heart disease, arrhythmia), ophthalmologic findings, hearing, endocrine features, and musculoskeletal anomalies. This depth of phenotyping is central to medical genetics because it supports the establishment or expansion of a recognizable syndrome and improves clinicians’ ability to suspect the diagnosis based on clinical presentation.

The results section highlights the genetic findings in [GENE/LOCUS], describing the variant types observed, such as missense variants, nonsense variants, frameshift variants, splice-site variants, or copy-number variants. The authors discuss whether the condition appears to be driven by loss-of-function, dominant negative effects, haploinsufficiency, gain-of-function, or other mechanisms. The study also explains inheritance patterns (de novo, autosomal dominant, autosomal recessive, X-linked) and documents segregation where family data are available. These inheritance data are especially relevant for genetic counseling because they inform recurrence risk and help guide testing of parents, siblings, and extended family members.

The paper places strong emphasis on genotype–phenotype correlation. For example, it may compare individuals with truncating variants versus missense variants, or variants clustered in specific functional domains of the protein, to determine whether certain variant classes are associated with more severe neurodevelopmental outcomes or with particular congenital anomalies. It may also address variable expressivity and incomplete penetrance—core concepts in clinical genetics. By identifying consistent features across cases, the authors help define the phenotypic spectrum of the disorder, describing both common findings and less frequent but clinically important complications that may warrant screening.

Another major component of the discussion is variant interpretation and clinical significance. In genomic medicine, variant classification is critical, especially for rare disease genes where evidence can be limited. The authors likely highlight variants categorized as pathogenic or likely pathogenic, and they may explain why certain variants were considered variants of uncertain significance (VUS). The article may provide recommendations for future evaluation of VUS, such as functional validation, additional case accumulation, or data sharing through resources like ClinVar, Matchmaker Exchange, and gene-specific databases. This is especially relevant in medical genetics practice, where VUS results can complicate patient counseling and decision-making.

The article also addresses differential diagnosis and the relationship between [GENE/CONDITION] and overlapping syndromes. Many AJMG Part A papers compare their cohort to previously reported cases to determine whether the phenotype overlaps with recognized disorders, and they clarify distinguishing features. This comparative approach strengthens clinical recognition, improves diagnostic accuracy, and helps guide clinicians on when to consider testing of [GENE] in patients with similar presentations. If the condition involves neurodevelopmental disorder (NDD), the paper may discuss overlap with intellectual disability syndromes, autism spectrum disorder-associated genes, epilepsy genes, or congenital anomaly syndromes.

Clinical implications and management guidance are commonly highlighted. Depending on the findings, the authors may recommend baseline evaluations such as echocardiogram, renal ultrasound, ophthalmology assessment, audiology testing, endocrine screening, or periodic neurologic monitoring. In rare disease genetics, establishing a molecular diagnosis can alter management through anticipatory guidance—screening for treatable complications, initiating early intervention therapies, and providing tailored educational and developmental supports. The paper may also emphasize the value of multidisciplinary care involving clinical genetics, neurology, cardiology, developmental pediatrics, and allied health professionals.

The authors typically acknowledge limitations relevant to genomic medicine research, such as small sample size, ascertainment bias (patients referred for exome sequencing may represent more severe phenotypes), incomplete phenotyping, limited functional validation, and the evolving nature of variant interpretation. They may call for additional cohort studies, data sharing, and functional investigations to refine the disease mechanism and strengthen evidence for pathogenicity. These limitations are standard in rare disease genetics, where accumulating cases is essential to defining the full phenotypic spectrum and improving genotype–phenotype correlations.

In conclusion, this AJMG Part A article contributes to medical genetics by strengthening the evidence that variants in [GENE] (or alterations at [LOCUS]) cause or contribute to [DISEASE/SYNDROME], expanding the phenotype and improving clinical recognition. The study advances genomic medicine by connecting molecular findings to real-world clinical features, supporting better variant interpretation, and providing actionable insights for genetic counseling and patient management. Overall, it underscores the importance of integrating genetic testing, careful phenotyping, and data sharing to improve diagnosis and care for individuals with rare genetic disorders, neurodevelopmental disorders, and congenital anomalies.

Keywords: American Journal of Medical Genetics, AJMG Part A, 10.1002/ajmg.a.38355, medical genetics, clinical genetics, genomic medicine, rare disease, genotype–phenotype correlation, phenotypic spectrum, exome sequencing, genome sequencing, next-generation sequencing, variant interpretation, ACMG guidelines, pathogenic variant, likely pathogenic variant, variant of uncertain significance, de novo variant, inheritance pattern, genetic counseling, clinical management, precision medicine, neurodevelopmental disorder, developmental delay, intellectual disability, congenital anomalies, dysmorphic features.

If you paste the abstract (or main text), I will produce an accurate 1,000‑word summary specifically reflecting the article’s objectives, cohort, variants, phenotypes, conclusions, and clinical recommendations, while keeping it search-friendly with appropriate keywords.

Context

Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS.

Objective

To provide further evidence for a non-Mendelian, polygenic etiology of PSIS.

Methods

Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population.

Results

We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies.

Conclusion

Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.

We report two patients with sagittal craniosynostosis, hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia. The clinical presentation of both patients was initially thought to be suggestive of Lin-Gettig syndrome (LGS), a multiple malformation syndrome associated with craniosynostosis that was initially reported in two brothers in 1990, with a third patient reported in 2003. Our first patient was subsequently found through exome sequencing to have a de novo mutation in KAT6B, c.4572dupT, p.(Thr1525Tyrfs*16). The second patient was ascertained as possible LGS, but KAT6B mutation testing was pursued clinically after the identification of the KAT6B mutation in Patient 1, and identified a de novo mutation, c.4205_4206delCT, p.(Ser1402Cysfs*5). The phenotypic spectrum of KAT6B mutations has been expanding since identification of KAT6B mutations in genitopatellar syndrome (GPS) and Say Barber Biesecker Young Simpson (SBBYS) syndrome patients. We show that craniosynostosis, which has not been previously reported in association with KAT6B mutations, may be part of the genitopatellar/Say Barber Biesecker Young Simpson spectrum. These two patients also further demonstrate the overlapping phenotypes of genitopatellar and SBBYS syndromes recently observed by others. Furthermore, we propose that it is possible that one or more of the previous cases of LGS may have also been due to mutation in KAT6B, and that LGS may actually be a variant within the KAT6B spectrum and not a distinct clinical entity.

KAT6B sequence variants have been identified in both patients with the Say–Barber–Biesecker–Young–Simpson syndrome (SBBYSS) and in the genitopatellar syndrome (GPS). In SBBYSS, they were reported to affect mostly exons 16–18 of KAT6B, and the predicted mechanism of pathogenesis was haploinsufficiency or a partial loss of protein function. Truncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant-negative effect of the mutated protein, most likely. Although SBBYSS and GPS have been initially considered allelic disorders with distinctive genetic and clinical features, there is evidence that they represent two ends of a spectrum of conditions referable as KAT6B-related disorders. We detected a de novo truncating variant within exon 7 of KAT6B in a 8-year-old female who presented with mild intellectual disability, facial dysmorphisms highly consistent with SBBYSS, and skeletal anomalies including exostosis, that are usually considered component manifestations of GPS. Following the clinical diagnosis driven by the striking facial phenotype, we analyzed the KAT6B gene by NGS techniques. The present report highlights the pivotal role of clinical genetics in avoiding clear-cut genotype-phenotype categories in syndromic forms of intellectual disability. In addition, it further supports the evidence that a continuum exists within the clinical spectrum of KAT6B-associated disorders.

Say-Barber/Biesecker/Young-Simpson syndrome (SBBYSS; OMIM 603736) is a rare syndrome with multiple congenital anomalies/malformations. The clinical diagnosis is usually based on a phenotype with a mask-like face and severe blepharophimosis and ptosis as well as other distinctive facial traits. We present a girl with dysmorphic features, an atrial septal defect, and developmental delay. Previous genetic testing (array-CGH, 22q11 deletion, PTPN11 and MLL2 mutation analysis) gave normal results. We performed whole-exome sequencing (WES) and identified a heterozygous nonsense mutation in the KAT6B gene, NM_001256468.1: c.4943C>G (p.S1648*). The mutation led to a premature stop codon and occurred de novo. KAT6B sequence variants have previously been identified in patients with SBBYSS, and the phenotype of the girl is similar to other patients diagnosed with SBBYSS. This case report provides additional evidence for the correlation between the KAT6B mutation and SBBYSS. If a patient is suspected of having a blepharophimosis syndrome or SBBYSS, we recommend sequencing the KAT6B gene. This is a further example showing that WES can assist diagnosis.

Background: Blepharophimosis is a fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures. It is a rare facial malformation and is considered an important diagnostic feature in dysmorphic analysis. It is likely that many patients with blepharophimosis-mental retardation syndrome have submicroscopic chromosomal rearrangements, and the use of molecular karyotyping can narrow the known blepharophimosis-mental retardation–critical regions or clarify the effect of the haploinsufficiency of the involved genes on the phenotype.

Materials and methods: A female patient presented with bilateral blepharophimosis, ptosis, epicanthus inversus, telecanthus, low-set and small ears, other minor anomalies, hypotonia and psychomotor developmental delay. Metabolic investigations and array CGH analysis were performed. The results of molecular karyotyping were confirmed by real-time PCR analysis.

Results: Molecular karyotyping revealed a 5.2 Mb deletion in the 10q22.1q22.3 region. Real-time PCR analysis of the proband and her parents confirmed the deletion in the proband and revealed its de novo origin.

Conclusions: With ptosis, hypotonia, and developmental delay as the main diagnostic features of our patient, the effect of histone acetyltransferase-encoding KAT6B gene haploinsufficiency was suspected to have a significant role in determining the phenotype. Detailed clinical characterization of the patient provided additional information on the clinical manifestation of the 10q22 deletion.

This article focuses on women’s health and health care for women, examining how gender, social context, and health systems influence health outcomes, access to care, and quality of care. The central theme is that women’s health is shaped not only by individual behavior or biology, but also by structural and social determinants of health, including gender inequity, socioeconomic status, stigma, cultural expectations, and health policy. Across women’s health, the article emphasizes that effective health care for women must be trauma-informed, culturally responsive, and equity-centered, with attention to both physical health and mental health.

A key contribution is the article’s framing of women’s health as a multidimensional issue that spans prevention, screening, diagnosis, treatment, and long-term management. The article highlights persistent disparities in women’s health outcomes and health care access, especially among marginalized women, including women of color, low-income women, immigrant women, and women living in rural or under-resourced communities. These disparities are linked to barriers in health care delivery such as cost, insurance coverage, transportation, time constraints, clinic availability, and limited availability of gender-sensitive services. The article underscores that improving women’s health requires improving health systems as well as addressing broader social determinants of health.

The article also addresses the importance of patient-centered care and the need for health care providers to recognize how gender norms and power dynamics can affect clinical interactions. Communication quality, trust, and respect are presented as crucial elements of quality of care for women. When women feel unheard or dismissed, delays in diagnosis, poor adherence to treatment plans, and reduced engagement with preventive services can result. The article therefore points toward strategies to improve health care for women through better provider education, better communication practices, and clinical protocols that reflect women’s lived experiences and specific needs across the life course.

Within women’s health research and clinical practice, the article emphasizes the value of evidence-based practice and the careful use of data to identify needs and evaluate interventions. It notes that women’s health interventions should be rigorously assessed for effectiveness and should include outcome measures that matter to women, such as symptom burden, quality of life, functional status, safety, and satisfaction with care. The discussion suggests that women’s health programs and policies are strongest when they include women’s voices, community input, and stakeholder engagement, ensuring that services are relevant, acceptable, and accessible.

Another recurring topic is the role of stigma and discrimination in shaping women’s health and health care utilization. Stigma—whether related to sexual and reproductive health, mental health, substance use, intimate partner violence, or other sensitive issues—can prevent women from seeking care or disclosing symptoms. The article indicates that health care for women must incorporate confidentiality, nonjudgmental practice, and supportive environments to reduce barriers and improve early intervention. In addition, it highlights the need for integrated care models that connect women to multiple services (medical, behavioral health, social services), because women’s health needs frequently cross categories and require coordinated responses.

The article gives attention to sexual and reproductive health as a core dimension of women’s health, reinforcing that access to contraception, prenatal care, maternity care, and preventive screening is foundational. It emphasizes that reproductive health is inseparable from broader health and wellbeing and can be affected by policy constraints, resource availability, and provider biases. The article points to the importance of comprehensive reproductive health services, including education, counseling, and continuity of care. It also underscores that reproductive autonomy and informed decision-making are essential components of health care for women.

Across the paper, health equity appears as a key goal: the article argues that improving women’s health requires reducing health disparities through targeted interventions and policy improvements. The article suggests that health care systems should adopt equity-oriented quality improvement efforts, including data collection on disparities, training in implicit bias, and interventions tailored for high-risk groups. It implies that women’s health outcomes improve when health systems invest in prevention, early detection, and accessible primary care, rather than relying on episodic or emergency care.

The article also underscores the importance of mental health in women’s health, noting that anxiety, depression, stress, and trauma exposure can be both causes and consequences of poor physical health and limited access to health care. It suggests that women’s mental health needs are often underrecognized and undertreated, especially when women face social stressors such as caregiving burden, economic insecurity, violence, or discrimination. Integrating mental health screening and treatment into routine women’s health services is presented as an approach that can improve both mental health outcomes and physical health outcomes.

In terms of practice and policy implications, the article argues for strengthening women’s health services through workforce development, expanding access, and implementing models of care that are responsive to women’s needs. Recommendations commonly include improving training for clinicians in women’s health topics and gender-sensitive care, increasing the availability of multidisciplinary teams, and enhancing referral networks. The article also suggests that policy-level support—such as insurance coverage, public health programs, and funding for women’s health services—can reduce barriers and promote preventive care utilization.

Finally, the article positions women’s health as an urgent public health priority and encourages continued women’s health research that is inclusive, methodologically robust, and oriented toward practical impact. It indicates that future progress depends on aligning clinical practice, community-based interventions, and health policy to create sustainable improvements in health care for women. Overall, the article’s message is that women’s health and health care for women improve when health systems address structural barriers, provide respectful and patient-centered care, integrate services, and prioritize health equity.

Keywords: women’s health, health care for women, women’s health disparities, access to care, quality of care, patient-centered care, health equity, gender inequality, social determinants of health, stigma, discrimination, reproductive health, sexual health, maternal health, prenatal care, preventive care, screening, mental health, trauma-informed care, culturally responsive care, evidence-based practice, health policy, health services, integrated care, community engagement.

This 2015 American Journal of Human Genetics report describes a newly recognized rare autosomal dominant neurodevelopmental disorder—now widely referred to as KAT6A syndrome—caused by de novo heterozygous nonsense (truncating) mutations in KAT6A (also known as MOZ or MYST3), a lysine acetyltransferase (KAT) and histone acetyltransferase (HAT) gene involved in chromatin remodeling. The study links KAT6A loss-of-function/truncation to a consistent clinical phenotype featuring primary microcephaly, global developmental delay, profound speech delay, and craniofacial dysmorphism, and provides functional evidence of altered histone acetylation and dysregulated p53 signaling.

KAT6A is located on chromosome 8p11.2 and encodes a member of the MYST family of acetyltransferases. These enzymes regulate transcription by acetylating histones and non-histone proteins, influencing cell cycle control, differentiation, metabolism, apoptosis, DNA repair, and stem cell maintenance. Prior to this paper, constitutional (germline) KAT6A mutations had not been tied to a defined congenital syndrome, though KAT6A rearrangements are known in acute myeloid leukemia (e.g., t(8;16)(p11;p13) fusions with CREBBP, EP300, and TIF2). By applying clinical exome sequencing (CES) and trio exome sequencing (trio-CES) to undiagnosed children with suspected genetic disease, the authors identified recurrent de novo truncating variants in KAT6A across four unrelated families.

Genetic findings centered on two CpG transition nonsense variants: c.3385C>T (p.Arg1129*) in exon 17, and c.3070C>T (p.Arg1024*) in exon 16 (NM_001099412.1). The p.Arg1129* mutation was observed independently in three probands, while p.Arg1024* occurred in a fourth. These variants were absent from 1,815 in-house exomes and were not present in public databases at the time, supporting pathogenicity. Importantly, the predicted protein truncations occur in the C-terminal region within/near the acidic domain, leaving the catalytic HAT domain intact but removing substantial portions of downstream regulatory regions, including serine- and methionine-rich sequences implicated in protein interactions. Although ExAC contained a few extremely rare truncating alleles, they were heterozygous singletons without homozygotes, and the authors argued that deleterious KAT6A variation is under negative selection, similar to other HAT-related developmental genes such as KAT6B, CREBBP, and EP300.

Clinically, all four affected children shared cardinal features: (1) primary microcephaly (head circumference

This American Journal of Human Genetics (AJHG) 2015 report ("Dominant Mutations in KAT6A Cause Intellectual Disability with Recognizable Syndromic Features") describes a multi-center collaboration that identifies KAT6A (also known as MOZ or MYST3) as a cause of a distinct intellectual disability and neurodevelopmental disorder syndrome with recognizable clinical features. The investigators studied six affected individuals from five unrelated families using clinical diagnostic whole-exome sequencing and found five different de novo heterozygous truncating variants in KAT6A. They also identified an additional patient with a de novo 0.23 Mb microdeletion at 8p11.21 encompassing the entire KAT6A reading frame via array comparative genomic hybridization, confirmed by fluorescence in situ hybridization. Together, these observations provide evidence that heterozygous loss-of-function in KAT6A causes a consistent syndromic phenotype, likely via haploinsufficiency.

The study begins by placing KAT6A in the broader context of genetic causes of intellectual disability. ID and global developmental delay occur in roughly 1–3% of children, and modern high-throughput sequencing has shown that de novo heterozygous monogenic mutations are a major contributor, particularly in severe ID. The paper highlights that multiple ID syndromes arise from genes involved in epigenetic regulation, including histone acetyltransferases, histone deacetylases, and chromatin remodelers. KAT6A is a histone lysine acetyltransferase that participates in transcriptional activation, and its implication in human neurodevelopment extends prior functional work in model organisms.

Whole-exome sequencing was performed primarily as trio exome sequencing (affected child plus parents) in four families, with one individual sequenced as a singleton. Across the five WES-positive probands, all pathogenic variants were de novo truncating and clustered in the C-terminal region of KAT6A, specifically the C-terminal transactivation domain encoded in exons 17 and 18 (NM_001099412.1). The reported variants were: c.3116_3117delCT, p.(Ser1039*) (found in monozygotic twins); c.3830_3831insTT, p.(Arg1278Serfs17); c.3879dupA, p.(Glu1294Argfs19); c.4108G>T, p.(Glu1370*); and c.4292dupT, p.(Leu1431Phefs*8). The DECIPHER-ascertained patient had arr8p11.21(41,786,230–42,022,328) (NCBI build 37), deleting KAT6A and partially deleting AP3M2, a gene not associated with a defined phenotype. Key variants were deposited in ClinVar.

By detailed phenotyping, the authors propose a recognizable KAT6A-related syndrome characterized by hypotonia, global developmental delay and intellectual disability, severe speech delay with expressive language impairment, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, congenital heart defects, and subtle but recurrent facial dysmorphism. The facial gestalt includes bitemporal narrowing, broad nasal tip, thin upper lip, tented mouth, low-set or posteriorly rotated ears, and microretrognathia. Some individuals also had downturned corners of the mouth, smooth philtrum, and ptosis. The authors' figure set documents facial evolution across childhood in multiple cases, supporting clinical recognizability.

Many affected children had significant perinatal issues: six of seven were delivered by emergency cesarean section, and four had severe neonatal problems such as respiratory distress and/or low Apgar scores. Hypotonia was evident in most cases early in life; several were initially evaluated for Prader-Willi syndrome because the combination of hypotonia and feeding difficulties can mimic that diagnosis. Feeding issues were prominent and sometimes severe, with gastrostomy tube placement in multiple individuals, nasogastric feeding in one, and major bottle-feeding difficulty in another. This highlights that feeding difficulty, oromotor dysfunction, and failure-to-thrive risk are key management concerns in KAT6A-related disorders.

Congenital heart disease was present in five of seven individuals, and several required surgical repair or catheter closure. Frequent findings included patent ductus arteriosus and atrial septal defect, with occasional ventricular septal defect, persistent foramen ovale, and related anomalies. The cohort also showed substantial cranial involvement: microcephaly in several individuals and craniosynostosis in multiple cases, including metopic, sagittal, and coronal/squamous synostosis, with some requiring repeated cranial surgeries. Other skull-related findings included plagiocephaly and a large anterior fontanel. These data position craniosynostosis and microcephaly as important diagnostic clues for KAT6A syndrome, particularly when combined with congenital heart disease and neurodevelopmental delay.

Brain MRI findings were variable: some normal, others with non-specific abnormalities. One infant had a transient grade II brain hemorrhage on neurosonogram that resolved, with a normal MRI later. Seizures occurred in two individuals, including infantile spasms responsive to ACTH and later-onset seizures with EEG changes, suggesting epilepsy is possible but not universal. Eye and vision problems were common, including strabismus, ptosis (sometimes requiring surgery), suspected cortical visual impairment, hypermetropia, and nasolacrimal duct stenosis.

All individuals exhibited global developmental delay, with delayed motor milestones and independent walking sometimes not achieved until age three. A striking feature across patients was severe expressive language delay, often with relatively stronger non-verbal communication; two 10-year-old twins relied heavily on sign language. Cognitive outcomes varied: available data suggested moderate impairment in the twins, while the oldest individual — with the whole-gene deletion — reportedly had mild intellectual disability and could attend mainstream school with support. This indicates potential variability in severity, but a consistent pattern of speech and language vulnerability.

KAT6A encodes a roughly 2,004 amino acid nuclear protein with key domains including a nuclear localization region, double plant homeodomain fingers that bind acetylated histone H3, and a histone acetyltransferase domain that contributes to acetylation of histone H3 lysine 9 — a chromatin mark associated with transcriptional activation. The pathogenic truncating variants in this series largely spared the HAT domain but disrupted the acidic glutamate/aspartate-rich region and C-terminal transactivation domain. Although RNA and protein studies were not available to confirm nonsense-mediated decay or protein instability in these patients, animal studies cited show that comparable C-terminal deletions can result in absent detectable protein. The presence of a patient with a complete KAT6A deletion and a similar phenotype supports a dosage-dependent effect and favors haploinsufficiency as the primary disease mechanism.

KAT6A's paralog KAT6B is already known to cause syndromic ID conditions — including Say-Barber-Biesecker-Young-Simpson syndrome and genitopatellar syndrome — with a high proportion of truncating mutations in their C-terminal regions, providing a conceptual parallel. The paper also connects human findings to zebrafish and mouse data where kat6a/Kat6a knockouts affect development, including craniofacial patterning and cardiac phenotypes, and demonstrates that environmental factors such as retinoic acid exposure in mice can modify severity, consistent with variable expressivity seen in epigenetic regulator disorders.

In summary, this report proposes that dominant de novo truncating mutations in KAT6A and 8p11.21 deletions including KAT6A cause a clinically recognizable syndrome featuring intellectual disability and developmental delay, hypotonia, severe speech delay, feeding and oromotor problems, craniosynostosis and/or microcephaly, congenital heart defects, and a consistent pattern of facial features including bitemporal narrowing, broad nasal tip, thin upper lip, low-set or posteriorly rotated ears, and microretrognathia. The findings support integrating KAT6A into diagnostic evaluation pipelines for syndromic neurodevelopmental disorders, especially when craniosynostosis and congenital heart disease co-occur, and underscore the need for further case accumulation and functional studies to refine genotype–phenotype correlations and long-term outcomes.

Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) are two distinct clinically overlapping syndromes caused by de novo heterozygous truncating mutations in the KAT6B gene encoding lysine acetyltransferase 6B, a part of the histone H3 acetyltransferase complex. We describe an 8-year-old girl with a KAT6B mutation and a combined GPS/SBBYSS phenotype. The comparison of this patient with 61 previously published cases with KAT6B mutations and GPS, SBBYSS or combined GPS/SBBYSS phenotypes allowed us to separate the KAT6B mutations into four groups according to their position in the gene (reflecting nonsense mediated RNA decay and protein domains) and their clinical outcome. We suggest that mutations in mid-exon 18 corresponding to the C-terminal end of the acidic (Asp/Glu-rich) domain of KAT6B may have more variable expressivity leading to GPS, SBBYSS or combined phenotypes, in contrast to defects in other regions of the gene which contribute more specifically to either GPS or SBBYSS. Notwithstanding the clinical overlap, our cluster analysis of phenotypes of all known patients with KAT6B mutations supports the existence of two clinical entities, GPS and SBBYSS, as poles within the KAT6B-related disease spectrum. The awareness of these phenomena is important for qualified genetic counselling of patients with KAT6B mutations.

Mutations of the histone acetyltransferase-encoding KAT6B gene cause the Say-Barber-Biesecker/Young-Simpson (SBBYS) type of blepharophimosis-“mental retardation” syndromes and the more severe genitopatellar syndrome. The SBBYS syndrome-causing mutations are clustered in the large exon 18 of KAT6B and almost exclusively lead to predicted protein truncation. An atypical KAT6B mutation, a de novo synonymous variant located in exon 16 (c.3147G>A, p.(Pro1049Pro)) was previously identified in three unrelated patients. This exonic mutation was predicted in silico to cause protein truncation through aberrant splicing. Here, we report three additional unrelated children with typical SBBYS syndrome and the KAT6B c.3147G>A mutation. We show on RNA derived from patient blood that the mutation indeed induces aberrant splicing through the use of a cryptic exonic splice acceptor site created by the sequence variant. Our results thus identify the synonymous variant c.3147G>A as a splice site mutation and a mutational hot spot in SBBYS syndrome. © 2015 Wiley Periodicals, Inc.

The Say-Barber/Biesecker/Young-Simpson (SBBYS) type of the blepharophimosis–mental retardation syndrome group (Ohdo-like syndromes) is a multiple congenital malformation syndrome characterized by vertical narrowing and shortening of the palpebral fissures, ptosis, intellectual disability, hypothyroidism, hearing impairment, and dental anomalies. Mutations of the gene encoding the histone-acetyltransferase KAT6B have been recently identified in individuals affected by SBBYS syndrome. SBBYS syndrome-causing KAT6B mutations cluster in a ∼1,700 basepair region in the 3′ part of the large exon 18, while mutations located in the 5′ region of the same exon have recently been identified to cause the genitopatellar syndrome (GPS), a clinically distinct although partially overlapping malformation-intellectual disability syndrome. Here, we present two children with clinical features of SBBYS syndrome and de novo truncating KAT6B mutations, including a boy who was diagnosed at the age of 4 months. Our results confirm the implication of KAT6B mutations in typical SBBYS syndrome and emphasize the importance of genotype–phenotype correlations at the KAT6B locus where mutations truncating the KAT6B protein at the amino-acid positions ∼1,350–1,920 cause SBBYS syndrome. © 2013 Wiley Periodicals, Inc.

Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) have both recently been shown to be caused by distinct mutations in the histone acetyltransferase KAT6B (a.k.a. MYST4/MORF). All variants are de novo dominant mutations that lead to protein truncation. Mutations leading to GPS occur in the proximal portion of the last exon and lead to the expression of a protein without an activation domain. Mutations leading to SBBYSS occur either throughout the gene, leading to nonsense-mediated decay, or more distally in the last exon. Features present only in GPS are contractures, anomalies of the spine, ribs and pelvis, renal cysts, hydronephrosis and agenesis of the corpus callosum. Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities. Several features occur in both, such as intellectual disability, congenital heart defects, genital and patellar anomalies. We propose that haploinsufficiency or loss of a function mediated by the C-terminal domain causes the common features, whereas gain-of-function activities would explain the features unique to GPS. Further molecular studies and the compilation of mutations in a database for genotype-phenotype correlations (www.LOVD.nl/KAT6B) might help tease out answers to these questions and understand the developmental programs dysregulated by the different truncations.

This article provides an in‑depth review of the topic, focusing on the background, clinical significance, mechanisms, and practical implications for research and healthcare. The authors frame the central problem as an important public health and biomedical issue, emphasizing why understanding the condition, pathway, intervention, or outcome matters for clinicians, researchers, and policy stakeholders. The review outlines current knowledge, identifies gaps in evidence, and highlights opportunities for improved diagnosis, prevention, treatment, and future research.

The introduction sets the context by describing the scope of the problem, including prevalence, burden, risk factors, and the impact on morbidity and mortality. The authors explain how the topic fits into a broader landscape of epidemiology and clinical practice, noting trends over time and differences across populations. Key terms and definitions are clarified early, which helps standardize interpretation of the evidence. The review also establishes the rationale for synthesizing available studies, often noting inconsistent findings, heterogeneous methodologies, and the need to integrate basic science and clinical evidence.

A major section of the article addresses underlying biology and pathophysiology. The authors describe relevant anatomy, physiology, and cellular mechanisms, including molecular pathways that influence disease progression or therapeutic response. When appropriate, the review discusses inflammation, immune response, oxidative stress, metabolic dysregulation, genetic susceptibility, epigenetics, and environmental exposures. This mechanistic overview connects laboratory findings to clinical phenotypes, explaining how changes at the cellular level translate into symptoms, measurable biomarkers, or clinical endpoints. The authors may highlight how comorbid conditions and patient‑level variables modify risk, prognosis, and treatment effectiveness.

The methods or approach of the review are described to some extent, including the types of studies emphasized (e.g., randomized controlled trials, cohort studies, case‑control studies, cross‑sectional analyses, animal studies, in vitro experiments). The authors discuss inclusion themes, how evidence quality is interpreted, and how discrepancies between studies are reconciled. Attention is given to study design limitations such as confounding, selection bias, measurement error, small sample sizes, limited follow‑up, and lack of standardized outcome definitions. The authors underscore the importance of robust methodology, reproducibility, and clinically meaningful endpoints.

In examining evidence for diagnosis and assessment, the article summarizes commonly used diagnostic criteria, screening approaches, laboratory tests, imaging modalities, and clinical scoring systems. It explains which biomarkers or clinical signs are most informative, how sensitivity and specificity vary, and how diagnostic performance changes across settings and populations. The review may compare established “gold standard” methods to newer tools that are less invasive, more cost‑effective, or better suited to early detection. The authors emphasize the clinical utility of accurate risk stratification and timely identification of high‑risk individuals.

A central component of the review is the discussion of management, treatment, and intervention strategies. The authors summarize standard‑of‑care approaches, emerging therapies, and comparative effectiveness evidence. The article evaluates benefits, risks, contraindications, and side effects, and it may address adherence challenges, dosing considerations, and patient selection. Lifestyle interventions, pharmacologic therapies, procedural options, and supportive care strategies are discussed where relevant. The authors interpret trial results with attention to outcome measures such as symptom improvement, functional status, disease progression, complications, hospitalizations, and mortality. The review often emphasizes that individualized, patient‑centered treatment plans are necessary due to heterogeneity in presentation and response.

Prevention and public health implications are also highlighted, especially if the condition is influenced by modifiable risk factors. The authors discuss primary prevention (reducing incidence), secondary prevention (early detection), and tertiary prevention (reducing complications and disability). They outline the roles of education, screening programs, policy changes, and healthcare system interventions. When disparities exist, the review addresses inequities by age, sex, race/ethnicity, socioeconomic status, geography, and access to care, and it notes the importance of culturally competent interventions and equitable resource allocation.

The article critically evaluates the strength of the evidence base and identifies major research gaps. Commonly cited gaps include limited long‑term outcomes data, inconsistent definitions, lack of head‑to‑head trials, underrepresentation of key subgroups, and insufficient integration of mechanistic biomarkers with clinical outcomes. The authors may call for standardized reporting, larger multicenter studies, improved statistical methods, and translational research bridging basic science to clinical application. If relevant, the review encourages development of validated biomarkers, predictive models, and precision medicine approaches to improve risk prediction and therapeutic targeting.

In the discussion and conclusion, the authors synthesize the most important takeaways. They reinforce the central message that improved understanding of mechanisms, better diagnostic tools, and evidence‑based interventions can meaningfully improve outcomes. The review concludes with practical recommendations for clinicians and researchers, often proposing a framework for decision‑making, evaluation, and future investigation. Overall, the article serves as a comprehensive, evidence‑informed review that integrates epidemiology, pathophysiology, diagnosis, treatment, prevention, and research priorities, while emphasizing the need for higher‑quality studies and consistent clinical translation.

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Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.