Contribution of Copy Number Variants and Cumulative Genetic Load to Autism Spectrum Disorders: Integrative Insights from Chromosomal Microarray Analysis

Genetic Heterogeneity in Autism Spectrum Disorder: Diagnostic Yield, Recurrent Genes, and Rare Variant-Phenotype Associations from Whole-Exome Sequencing

Autism spectrum disorder (ASD) is genetically heterogeneous, involving rare and common variants that disrupt neurodevelopmental pathways. To explore this complexity, we performed whole-exome sequencing in children with ASD. Clinical phenotypes were systematically recorded, and severity was classified according to DSM-5 criteria. Variants were interpreted using ACMG guidelines, with recurrence analysis to identify genes shared across individuals and cohort enrichment testing against gnomAD. To examine genotype-phenotype relationships, we applied SKAT/SKAT-O across 16 phenotypes after covariate adjustment. Among 25 included individuals, pathogenic or likely pathogenic variants were found in 9, yielding a diagnostic yield of 36%. These involved genes linked to neurodevelopmental, epileptic, metabolic, and syndromic disorders. Recurrence analysis identified 586 genes present in at least two individuals, with PABPC1, GTF2I, PCLO, PKD1, and EP400 being the most frequent. SKAT/SKAT-O revealed the strongest burden associations for motor delay, aggressive behavior, mutism, anxiety, unresponsiveness to spoken voice, digestive disorder, and sleep disturbances, with limited overlap across phenotypes. Several recurrent genes also showed phenotype-specific associations. Overall, this integrative WES study provides clinically actionable diagnoses, highlights recurrent genes, and uncovers phenotype-specific signals, supporting convergent pathways with gene-level heterogeneity.

Chromosomal Microarray Analysis in Pediatric Patients with Neurodevelopmental Disorders and Congenital Anomalies: A Two-Center Experience

Chromosomal microarray analysis (CMA) is a first-tier diagnostic tool for children with neurodevelopmental disorders and congenital anomalies; however, interpretation of variants of uncertain significance (VUS) remains challenging. This study aimed to characterize the copy number variant (CNV) spectrum in pediatric patients with congenital anomalies and/or dysmorphic features, focusing on VUS interpretation through segregation analysis and detailed phenotype–genotype correlation. We retrospectively evaluated 28 pediatric patients with abnormal CMA results referred to two tertiary genetics clinics between 2021 and 2022. Indications included neurodevelopmental delay, intellectual disability, dysmorphism, and/or congenital anomalies. CNVs were classified according to 2020 ACMG/ClinGen standards. Parental segregation analysis was performed for 15 CNVs in 13 families, with particular attention to gene disruption caused by CNV breakpoints. The cohort included 16 males and 12 females, with a mean age of 5.28±4.39 years. Thirty-four CNVs were identified, including 14 deletions and 20 duplications; seven were pathogenic/likely pathogenic and 27 were VUS. Segregation analysis identified five de novo, six maternal, and four paternal variants. A 2q22.2 gain disrupting KYNU at intron 12 was identified in a patient with VACTERL-like features. Three patients had additional karyotypic abnormalities, highlighting the complementary role of CMA. A de novo 4p16.3 duplication disrupting both HTT and ADD1 was also identified. Our findings highlight the importance of detailed phenotyping, breakpoint analysis, and segregation studies in interpreting CNVs, particularly VUS and rare intragenic disruptions. Integrating genomic findings with clinical features and inheritance patterns may improve phenotype–genotype correlation and support the identification of candidate loci.

Genomic landscape of rare variants in a Chinese autism cohort and discovery of novel risk genes.

A whole-genome sequencing analysis of 3109 samples across 1033 Chinese ASD families expands the ASD genetic landscape and suggest convergent pathogenic axes involving transcriptional regulation, synaptic signaling and plasticity, and neuroimmune interactions.

Chromosome Microarray Analysis of 3832 Patients over 15 Years Confirms Genome-Wide Copy Number Variation in Patients with Developmental Disabilities Including Autism

Neurodevelopmental Impact of Copy Number Variants in Patients With Treatment-Resistant Schizophrenia.

Copy number variations (CNVs) are a major contributor to the etiology and phenotypic variability in schizophrenia. CNVs are also independently associated with certain neurological, cognitive, and behavioral conditions, yet their role in early neurodevelopment in the context of treatment-resistant schizophrenia remain largely unexplored. This study aimed to investigate the contribution of neurodevelopmental CNVs to early development among individuals with treatment-resistant schizophrenia (TRS). We conducted a structured, systematic, retrospective record review within a case-control analytic framework. Our cases were the group of neurodevelopmental disorder (NDD) CNV carriers (N = 25) identified in the Pennsylvania State Hospital (PASH) cohort of individuals with treatment resistant psychotic symptoms; non-CNV controls were demographically matched individuals with treatment resistant psychotic symptoms (N = 24) from the PASH cohort. We examined the differences in early NDD phenotypes between cases and controls. CNV carriers had a higher total NDD burden score compared to non-CNV controls (z = 2.20, unadjusted p = 0.03, adjusted p = 0.08). Learning disabilities were significantly more prevalent among CNV carriers compared to non-CNV controls (χ2 = 13.437, df = 1, unadjusted p = 0.0002, adjusted p = 0.0015), with 88% of CNV carriers having a history of learning disabilities relative to 38% of non-CNV controls. CNVs carriers with TRS had a higher prevalence of early NDDs compared to non-CNV controls, particularly in learning disabilities. Prospective studies are needed to elucidate the mechanisms linking CNVs, neurodevelopmental phenotypes, and disease progression in treatment resistant schizophrenia.

Higher frequencies of CNV deletions in bipolar disorder among Chinese Population.