搜索结果：HGG advances

Reirradiation has re-emerged as a viable salvage modality for recurrent central nervous system (CNS) tumors in the modern era of precision radiotherapy. Advances in image guidance, biological understanding of normal-tissue repair, and integration of targeted systemic agents have expanded its therapeutic window. The 2025 ISRS meta-analysis (62 studies; n = 2640) established a median overall survival (OS) of ~ 10.2 months after re-irradiation (re-RT) of recurrent HGG, confirming that focal single-fraction SRS (16 Gy × 1) or hypofractionated SRS (25 Gy/5 fx) achieves optimal tumor control with acceptable neurologic toxicity (7% vs 4%). EQD₂ > 120-130 Gy markedly increases radionecrosis risk (p = 0.003). Integration of DNA-damage-repair (DDR) inhibitors, VEGF blockade, and tumor-treating fields (TTFields) is under active investigation. Re-RT in ependymoma, meningioma, and spinal tumors is also gaining renewed interest with proton and MR-guided adaptive techniques.

The inevitable progression of high-grade gliomas has prompted a need for data-backed identification of compromised tissue prior to detection on traditional serial imaging. Whole-brain magnetic resonance spectroscopy (WB-MRS) can fill this role to classify glioma progression prior to contrast enhancement. Voxel-level data can differentiate areas of perilesional tissue under supervised machine learning (ML) and has been shown to predict the likelihood of tumor progression within six months. In this study, we aim to improve the spatial utility of WB-MRS ML through unsupervised ML clustering for utility in intraoperative integration with existing neuronavigation platforms. This analysis involved 16 adult patients that developed recurrence of high-grade glioma (HGG) on serial imaging, including 13 with glioblastoma (GBM) and three with anaplastic astrocytomas. Postoperative WB-MRS images were used as data inputs. We investigated two unsupervised clustering methods to optimize the identification of compromised perilesional tissue from a previously published supervised model. All voxels within the new region of interest (ROI) are reclassified as future progression regardless of their classification from the supervised model. After hyperparameter tuning, Density-Based Spatial Clustering of Applications with Noise (DBSCAN) shows an area under the curve (AUC) of 0.942, while K-Means Clustering shows an AUC of 0.874. DBSCAN also shows a superior accuracy, specificity, sensitivity, and F1-score to the original supervised model alone. The incorporation of unsupervised clustering enhances the utility of WB-MRS for identifying compromised perilesional tissue and predicting high-grade glioma progression. Unsupervised clustering incorporates critical geospatial data and offers a more surgically relevant approach to visualizing tumor progression. Early detection of high-grade glioma recurrence remains a major limitation of current imaging modalities, restricting the ability to guide timely and precise interventions. While prior work has demonstrated that WB-MRS combined with supervised ML can identify metabolically abnormal tissue at risk for progression, these approaches lack spatial coherence and clinical usability. In this study, we introduce a hybrid pipeline integrating supervised voxel-wise predictions with unsupervised spatial clustering (DBSCAN and K-means) to refine recurrence mapping. This approach significantly improves classification performance and generates spatially contiguous, clinically interpretable regions of interest. Importantly, these outputs can be exported as DICOM overlays, enabling direct integration into neuronavigation systems. While still in pilot phase, this work advances WB-MRS from a predictive tool toward a clinically integrable platform, with potential applications in surgical planning, biopsy targeting, and longitudinal disease monitoring in patients with high-grade glioma.

Heterotaxy (HTX) is a congenital disorder characterized by abnormal left-right organ placement, often leading to severe congenital heart disease (CHD). Despite advances in sequencing, many CHD and HTX-associated genes remain functionally unvalidated, hindering effective clinical diagnosis and management. Here, we leveraged a high-throughput CRISPR-Cas9 screening approach in the Xenopus model to rapidly evaluate candidate genes identified from whole-exome sequencing of human CHD patients. Our screen identified Filamin B (FLNB), an actin-binding protein previously linked to skeletal disorders but not to ciliopathies or CHD. We identified 5 probands with CHD and HTX, 3 with recessive and 2 with damaging heterozygous variants in FLNB. Disrupting flnb in Xenopus reproduced key features of the human HTX phenotype, including defects in cardiac development and impaired motile cilia function. Rescue experiments confirmed the functional conservation of human FLNB, directly implicating actin cytoskeletal disruption in ciliogenesis and left-right patterning defects. Our results provide crucial evidence linking human FLNB dysfunction to ciliopathies and CHD and HTX.

Prosody perception is an often overlooked aspect of human language despite its importance in facilitating spoken language comprehension. Sensitivity to prosodic cues varies between individuals, and prosody perception skills are shown to be associated with various language- and reading-related outcomes. Despite the importance of prosody perception in human communication, its underlying biology is poorly understood. This study investigates the genetic architecture of prosody (speech rhythm) perception and explores its evolutionary roots. We conducted a GWAS of prosody (n = 1,501) as measured by scores on the Test of Prosody via Syllable Emphasis ("TOPsy"). GWAS results yielded 14 suggestive significant signals (p < 5.00 &#xd7; 10-6). Gene set enrichment analysis identified shared genetic architecture between human prosody perception and key vocal learning brain regions in songbirds, suggesting that human prosody perception may have evolutionary convergence in communication mechanisms in animal vocal learning. Additionally, cross-trait polygenic score analyses suggest shared genetic influences between prosody perception and both word reading and musical beat synchronization, emphasizing how genetics influence prosody perception and its associations with communication-, education-, and music-related traits. These initial efforts could inform advances in communication sciences and disorders as well as educational contexts.

Inherited retinal diseases (IRDs) comprise a diverse group of disorders that frequently lead to progressive vision impairment and blindness. Despite advances in genetic testing, a significant number of IRD cases remain genetically unsolved, often due to unidentified disease-associated genes or variants. This study reports additional cases for the newly discovered IRD genes of the AP-5 complex. A comprehensive ophthalmological evaluation was performed for all patients, including retinal imaging (multimodal imaging), visual field testing, and electroretinogram (ERG) testing. Whole-genome and -exome sequencing (WGS and WES) were performed for clinically unsolved IRD patients, and data were analyzed to identify underlying causal variants. The identified variants were subsequently validated using Sanger sequencing. Five unrelated patients from Europe and Iran were identified with a distinctive macular degeneration associated with bi-allelic variants in AP5Z1 (HGNC: 22197) and AP5B1 (HGNC: 25104), subunits of the vesicular fifth adaptor protein (AP-5) complex. The AP-5 complex is the part of the intracellular trafficking machinery thought to be involved in cellular homeostasis and lysosomal functioning in the retinal pigment epithelium (RPE). The identification of bi-allelic variants in two proteins of the AP-5 complex expand the characterization of AP-5 genes in sustaining and preserving normal macular function.

Keratinizing desquamative squamous metaplasia (KDSM) of the urinary tract is typically a sporadic condition with unclear etiology and treatment options. It is characterized by either a focal or widespread transition of normal urothelium of the bladder and ureters to a stratified squamous keratinizing epithelium. Four individuals from three generations of a single family were ascertained with a likely autosomal dominant form of syndromic KDSM. Whole-genome sequencing was performed on three affected individuals and a truncating variant (RARG NM_000966.6:c.1237C>T; NP_000957.1:p.Arg413&#x2217;) in the gene encoding retinoic acid receptor gamma (RAR&#x3b3;) was identified to be segregating with the phenotype. The truncating variant does not destabilize the transcript or protein produced from this allele but instead predicts the loss of half of helix 12 of RAR&#x3b3;, leading to reduced responsiveness of the receptor to all-trans retinoic acid via a dominant-negative mechanism. Mice heterozygous for the variant demonstrated upregulation of cytokeratin-10 in the bladder and ureteric epithelium consistent with keratinizing squamous metaplasia of the urothelium. The implicated dominant-negative mechanism reduces retinoic acid signaling via heterodimeric receptors that incorporate the variant &#x3b3; subunit and indicates that this condition may be addressable with high-dose retinoic acid receptor agonists.

Human brain evolution is hypothesized to be driven primarily by regulatory rather than protein-coding changes. Identifying evolutionary changes in regulatory elements, however, has been constrained by numbers and relationships of taxa and by methodology targeting conserved sequences. These approaches are independent of any experimental assessment of function and overlook potential neofunctionalization in less constrained regions. Here, we leveraged 243 primate genomes to apply a human branch-specific positive selection test to over 350,000 experimentally confirmed human brain-active cis-regulatory elements, identifying 8,522 elements under positive selection on the human lineage. Genes regulated by human positively selected elements showed differential expression between humans and macaques during fetal and adult stages compared to non-selected elements. Elements under positive selection that remained active across fetal and adult stages showed the strongest enrichment for genetic variants associated with neuropsychiatric conditions, including schizophrenia and bipolar disorder.

Bicuspid aortic valve (BAV) is the most common congenital heart lesion in adults and is often associated with thoracic aortic aneurysms and aortic stenosis. The genetic causes of most non-syndromic cases of BAV remain unknown. Pathogenic variants in COL1A1 or COL1A2, which encode type I collagen (COL1), cause osteogenesis imperfecta (OI), a rare disorder marked by bone fragility. Although aortic valve phenotypes, including BAV, have been described in OI, COL1 genes have not been implicated in sporadic BAV. We report rare COL1 variants in individuals with early-onset BAV (EBAV) complications. Whole-exome sequencing was performed in 272 non-syndromic BAV probands who developed valve or aortic complications before age 30 (EBAV) and 272 biological relatives. Variants were filtered by allele frequency, inheritance pattern, ClinVar classification, and in silico predictions. Participants with rare predicted damaging COL1 variants were recontacted to confirm phenotypes. Rare coding variants in COL1A1 (n = 5) and COL1A2 (n = 5) were identified in 10 (4%) EBAV probands, representing a 30-fold enrichment compared with European ancestry populations. Only two variants involved glycine substitutions in triple-helical domains. Affected probands presented with aortic regurgitation and/or thoracic aneurysms requiring repair and exhibited subtle connective tissue features such as joint hypermobility, recurrent fractures, or dental abnormalities. Predicted damaging COL1 variants are enriched in EBAV probands with features overlapping OI and Ehlers-Danlos syndrome, though involving different residues than those in OI. Genetic testing for these variants may help identify individuals who could benefit from personalized surveillance or targeted preventive strategies.

Rare genetic variation is considered a potential source of heritability in individuals with sporadic Alzheimer disease and related dementias (ADRD). The Variant-set test for association using annotation information (STAAR) framework leverages multiple functional annotations of genetic variants and combines association statistics from multiple variant aggregation-based methods, including burden, sequence kernel association test (SKAT), and aggregated Cauchy association test (ACAT-V), into a single measure of significance. Using whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP), we comprehensively examined the association of rare genetic variation with ADRD in 23,454 individuals (37% individuals affected by ADRD) and with cognitively healthy elder status in 13,292 individuals (13% cognitively healthy elders) from diverse populations via the STAAR framework. We identified several genes significantly associated with ADRD or cognitively healthy status. However, our analysis revealed several limitations within the STAAR framework incorporating ultra-rare variants with dichotomous outcomes. To enhance the robustness of the framework, we proposed several computational refinements, including creating a burden of ultra-rare variants and employing more precise annotations to match the expected mechanism. After implementing the proposed modifications, the association with ADRD for ZNF200 was no longer statistically significant (&#x3b1; = 1 &#xd7; 10-7), while TBX19, PLXNB2, CARD11, and LINC01880 remained significantly associated with cognitively healthy status. We identified and addressed the computational limitations in the STAAR framework that could lead to potential spurious results for ultra-rare variant aggregates with an extremely low cumulative minor-allele count. Our proposed refinements produced more robust results for associations with rare variants in the context of dichotomous outcomes.

Genetic summary statistics can be used in a variety of analyses, such as causal inference, genetic correlation, and risk scores, to provide insights into the genetic architecture of conditions and traits. However, complete statistics are often not reported limiting the utility of this data. Indeed, many post-hoc analyses of diseases require case and control allele frequencies (AFs), which are not always published. Here, we present methods and software to derive case and control AFs from genome-wide association study (GWAS) summary statistics using the odds ratio, case and control sample sizes, and either the total (case and control aggregated) AF or standard error (SE). In simulations and real data, derivations of case and control AFs using total AF are highly accurate while using SE underestimates AFs when covariates were included in the GWAS. While estimating case and control AFs using the total AF is preferred due to its high accuracy, SE is more commonly available. Thus, we developed a bias adjustment using gnomAD AFs as a proxy for true AFs reducing bias when using SE. The methods and software provided here expand the utility of publicly available genetic summary statistics and promote the reusability of genomic data. The R package Case-Control Allele Frequency Estimation (CCAFE) is freely available on Bioconductor and GitHub.

Oral and craniofacial diseases are common, yet their genetic basis and links to systemic health are incompletely understood. We performed genome-wide association analyses of 67 oral phenotypes in 500,348 FinnGen participants, identifying 102 genome-wide significant loci, including 45 previously unreported associations. 48 loci remained significant after category-level Bonferroni correction. Fine-mapping revealed 14 coding variants, such as a missense variant in USP31 for caries and in MANBA for oral leukoplakia, and a stop-gained variant in GPNMB for temporomandibular disorders. HLA analyses implicated DQA1 and DQB1 alleles in lichen planus and other mucosal disorders. We observed 378 statistically significant genetic correlations among oral traits, such as tooth loss and chronic apical periodontitis (rg = 0.91, 95% confidence interval (CI) [0.76, 1.05], P = 1.7 &#xd7; 10-34), and 419 significant correlations between oral and systemic diseases, including periodontal diseases with chronic laryngitis (rg = 0.97, 95% CI [0.58, 1.36], P = 1.2 &#xd7; 10-6) and bruxism with gastro-oesophageal reflux (rg = 0.51, 95% CI [0.38, 0.65], P = 1.1 &#xd7; 10-13). These results expand the catalog of oral disease loci, uncover Finnish-enriched risk alleles, and highlight shared inflammatory, immune, and structural pathways connecting oral and systemic health.

We report three individuals with bi-allelic variants in RNU6ATAC, which encodes the U6atac minor spliceosomal small nuclear RNA (snRNA), causing a multisystem minor spliceopathy. Through RNA sequencing analysis, we identified a distinctive excess of minor intron retention (MIR) in two unrelated individuals, which guided the identification of bi-allelic RNU6ATAC variants. The discovery cohort presented with variable multisystem manifestations. One individual presented with refractory epilepsy, microcephaly, developmental delay, ataxia, bilateral toe syndactyly, hypereosinophilia, and short stature, whereas the other exhibited failure to thrive, short stature, primary hypothyroidism, combined variable immunodeficiency, eosinophilic colitis, ichthyosis vulgaris, scoliosis, and chronic inflammatory demyelinating polyneuropathy without neurodevelopmental involvement. Despite organ-specific variation, both individuals displayed impaired growth and eosinophil-driven inflammation. Recently, we identified a third affected individual from an independent cohort whose phenotype bridges these features, combining microcephaly, growth failure with severe immunodeficiency, and skeletal abnormalities. The distinctive excess of MIR outliers in the discovery cohort supports minor spliceosome dysfunction, mirroring the molecular signature of RNU4ATAC-opathy. These findings nominate RNU6ATAC as a disease-associated gene, defining an expanded clinical spectrum of minor spliceopathies. Our study supports the power of integrating genomic and transcriptomic approaches for diagnosing splicing disorders and highlights the critical role of spliceosomal snRNAs in human disease.

The impact of clinical exome and genome sequencing (ES/GS) depends on the clinical setting. In the sequencing arm of a multifactor randomized clinical trial to evaluate broadening access, we assessed the diagnostic and inconclusive findings of ES as a "first-tier" test in 101 pediatric participants in whom suspicion of a genetic condition by primary care providers had prompted initial outpatient consultation in a pediatric genetics or neurology clinic. This implementation focused on the early stages of the diagnostic odyssey, capturing a clinically less-selected population with lower pre-test probability than traditional specialist cohorts. Variants were prioritized using phenotype-driven gene lists. After returning the results to participants, the clinical teams performed familial variant testing or additional phenotyping at their discretion, based on potential diagnostic benefit. We then implemented a multidisciplinary case conference in which the laboratory and clinical teams assessed additional clinical information. Initially, 57% of participants had non-negative reports: 5% had one or more variant findings considered explanatory for the presenting phenotype, with 52% having results initially classified as inconclusive. After family testing and/or phenotypic characterization, a total of 9% were considered positive/diagnostic, 10% were reclassified from inconclusive to negative, and 38% remained inconclusive. While ES, as a first-tier genetic test, can expedite some diagnoses, these results demonstrate challenges in early implementation. In this population, initial testing can leave substantial residual uncertainty, shifting the diagnostic odyssey rather than concluding it and necessitating factors such as parental testing, ongoing phenotyping, and reassessment of variants over time to resolve inconclusive results.

Polygenic scores (PGSs) have promising clinical applications for risk stratification, disease screening, and personalized medicine. However, most PGSs are trained on predominantly European ancestry cohorts and have limited portability to external populations. While cross-population PGSs have demonstrated greater generalizability than single-ancestry PGSs, they fail to properly account for individuals with recent admixture between continental ancestry groups. GAUDI, a recently proposed PGS method, overcomes this gap by leveraging local ancestry to estimate ancestry-specific effects, penalizing but allowing ancestry-differential effects. However, the modified fused LASSO approach used by GAUDI is computationally expensive and does not readily accommodate more than two-way admixture. To address these limitations, we introduce HAUDI, an efficient LASSO framework for admixed PGS construction. HAUDI reparameterizes the GAUDI model as a standard LASSO problem, allowing for extension to multiway admixture settings and far superior computational speed than GAUDI. In extensive simulations, HAUDI compares favorably to GAUDI while dramatically reducing computation time. In real data applications, HAUDI uniformly outperforms GAUDI across 18 clinical phenotypes, including total triglycerides, C-reactive protein, and mean corpuscular hemoglobin concentration, and shows substantial benefits over ancestry-agnostic PGSs for white blood cell count and chronic kidney disease. It is also substantially faster and more accurate than the recently proposed SDPR_admix method.

National guidelines from the US Preventive Services Task Force and the National Comprehensive Cancer Network recommend the use of family-health-history (FHH)-based risk assessment tools to guide genetic testing (GT) among women with an increased risk of inherited cancer and inform personalized cancer risk management. Prior research has focused on attitudes toward and decisions about initial uptake of GT in Black patients but little is known about the factors that impact the subsequent completion of GT after they have already provided consent. Using a community-based participatory research (CBPR) approach, we aimed to identify barriers and actionable strategies to improve GT completion offered through the Breast Health Assessment (BHA), an FHH screening tool administered at routine mammography visits. We conducted semi-structured interviews with 12 Black women who screened high-risk for inherited breast cancer and consented to GT through the BHA, but did not complete saliva sample collection. Thematic analysis revealed that lack of dedicated support throughout the BHA workflow emerged as a key obstacle to sample collection, whereas medical mistrust, shame, and limited knowledge were largely regarded as cultural barriers that had no impact on GT completion. Low utilization among participants reflected logistical challenges highlighting the need to evaluate multi-level implementation processes to better understand and address inequities in GT completion. Participants suggested implementing early educational outreach, culturally relevant messaging, and interpersonal touchpoints to promote GT uptake. By applying a CBPR approach, we translated these findings into actionable, equity-focused strategies to improve GT completion within a population genetic screening program.

Characterizing the relationship between DNA methylation and circulating proteins is critical to understanding the epigenetic regulation of the human plasma proteome. Here, we performed an epigenome-wide association study of 5,032 circulating proteins in 1,449 White and 315 Black participants from the Atherosclerosis Risk in Communities cohort. We identified 12,500 significant protein quantitative trait methylation (pQTM)-protein associations involving 1,647 proteins. Among 7,796 unique pQTMs, 14.7% were classified as cis-pQTMs, which were enriched for fundamental cellular processes, whereas trans-pQTMs were predominantly linked to immune-related functions. Trans-pQTMs also exhibited stronger associations with demographic, lifestyle, and clinical traits as compared with cis-pQTMs. We identified proteins such as GM2A and EPHB6, whose expression appears to be strongly associated with DNA methylation, suggesting potential as targets for epigenetic-based therapeutic interventions. These findings demonstrate the extensive impact of DNA methylation on the circulating proteome through cis- and trans-regulatory mechanisms and underscore the influence of population-level traits on epigenetic regulation. These findings highlight a broad impact of DNA methylation on circulating proteins through both cis- and trans-regulatory mechanisms and the roles of population-level phenotypes.

Genome sequencing (GS) has emerged as a transformative tool in the diagnosis of rare diseases with complex phenotypes. This technology uncovers structural, intronic, non-coding, and mitochondrial variants that traditional methods might miss, thereby facilitating the understanding of the underlying genomic basis of human disorders. We enrolled 10,305 patients with suspected rare diseases or hereditary cancer risk syndromes from 21 centers throughout Brazil. Their genomes were sequenced with short, paired-end reads, and diagnostic reports were provided for 9,448 of these patients. The overall diagnostic yield was 35.6%, and 4.6% of all positive reports had GS-exclusive findings (e.g., short copy-number variants overlapping fewer than three exons, deep intronic variants, short tandem repeat expansions, and mitochondrial structural variants-usually not detected by other diagnostic tests such as exome sequencing). Preliminary analysis of transcriptome sequencing (TS) or long-read GS combined with GS interpretation provided a small but welcome improvement in diagnostic yield (0.1% and 1.0% of positive reports, respectively). Almost 3,200 variant/phenotype interpretations were submitted to ClinVar. GS is proving to be an invaluable resource for shortening the diagnostic odyssey of patients with rare diseases, providing crucial genomic diagnostics, and enriching genetic databases with variant interpretations from underrepresented populations. Therefore, GS has the potential to significantly enhance the precision of healthcare in genetically diverse populations.

The CECR2 histone acetyl-lysine reader facilitates chromatin remodeling and plays a significant role in neurodevelopment. It resides within the cat eye syndrome (CES) critical region at 22q11.1q11.21. An increased copy number of this region, often as tetrasomy or a supernumerary chromosome, results in CES. The complex chromosomal arrangements and phenotypic variability have hampered the identification of the true cause(s) of CES. Patients and their clinical data were collected from multiple diagnostic and research laboratories. Exome or genome sequencing was performed in affected individuals and, when available, their relatives. Here, we describe six patients with a heterozygous single-nucleotide or small insertion/deletion variant in CECR2 and their clinical features. Variants were either loss-of-function [c.1734dupC:p.(Thr580Hisfs&#x2217;98), c.1819C>T:p.(Arg607&#x2217;), and c.2281C>T:p.(Arg761&#x2217;)] or missense in an intrinsically disordered and potentially critical region at the C terminus of the protein [c.4153C>G:p.(Gln1385Glu), c.4254C>G:p.(Phe1418Leu), and c.4283A>G:p.(Gln1428Arg)]. The main clinical features were delayed growth, relatively small head circumference, developmental delay, and speech issues/delay. Other clinical findings were variable and included intellectual disability; feeding problems; facial dysmorphism; cleft lip/palate; brain, ear, heart, or other organ abnormalities; behavioral abnormalities; and epilepsy. There was significant overlap with common CES features, including ear, heart, and brain abnormalities, intellectual disability, and growth restriction. In conclusion, we characterize a CECR2-associated neurodevelopmental disorder. The consistent molecular and clinical overlap with CES supports CECR2's role in the CES phenotype. These findings implicate diverse variant types in related neurodevelopmental disorders, underscoring CECR2's dosage sensitivity and essential function in epigenetic regulation during development.

Chromatin regulation is critical for neurodevelopment, and its disruption has emerged as a key pathogenic mechanism in neurodevelopmental disease, including autism spectrum disorder (ASD), a condition known for genetic and phenotypic heterogeneity. We previously identified an ASD gene, KDM5A, encoding a histone H3 lysine 4 demethylase, and reported de novo and inherited variants in nine individuals with severe ASD and other neurodevelopmental phenotypes. Here, we expand the genetic and phenotypic spectrum of KDM5A-related neurodevelopmental disorders and investigate the functional impact of identified variants. Through international collaborations, we assembled a cohort of 24 additional individuals from 21 families with rare, protein-altering KDM5A variants. All individuals presented with severe speech impairment and intellectual disability, often alongside ASD and other neurodevelopmental features. The variants include missense, nonsense, frameshift, and splice site, distributed across nearly all functional domains of the protein. Structural modeling revealed localized conformational disruptions, particularly at conserved residues in enzymatic or chromatin-interacting domains. For a subset of variants, we demonstrated reduced KDM5A protein levels in cell lines derived from affected individuals. Transcriptomic profiling revealed variant-specific gene expression changes, most pronounced in variants affecting the PLU1 chromatin-binding motif and the Jumonji C domain of the enzymatic core. American College of Medical Genetics and Genomics-guided reclassification supported pathogenicity for the majority of variants, including multiple upgrades from uncertain significance to pathogenic or likely pathogenic. Together, these findings implicate diverse KDM5A alleles in a rare but recurrent form of ASD and establish KDM5A as a key regulator of neurodevelopment and chromatin-mediated ASD pathogenesis.