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

Abstract

Autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs) are characterized by a complex genetic architecture involving both rare high-impact variants and cumulative low-effect alterations. The contribution of borderline copy number variants (CNVs) to disease susceptibility and phenotypic variability remains incompletely understood. Reflecting a real-world clinical setting rather than a prospectively recruited research cohort, we performed a retrospective analysis of a tertiary care registry comprising 328 individuals referred for suspected ASD or NDDs who underwent array comparative genomic hybridization (a-CGH), identifying 612 CNVs classified according to ACMG/ClinGen guidelines. CNVs were evaluated by type, size, genomic distribution, and clinical correlation, and patients were stratified based on CNV burden and the presence of borderline variants. Duplications were more frequent than deletions, and medium-sized CNVs (100–500 kb) were the most common. Borderline CNVs represented the largest category. Within this descriptive cohort, increased CNV burden, in both number and cumulative genomic size, co-occurred more frequently in individuals with severe phenotypes, including ASD with intellectual disability, epilepsy, and broader NDDs. Individuals with isolated ASD showed a lower burden and enrichment of small borderline variants, which often co-occurred alongside CNVs. In contrast, severe phenotypes were frequently associated with single large pathogenic variants. Recurrent loci included 15q11.2–q13, 16p11.2, and 22q11.21. Overall, these exploratory observations from a real-world clinical registry illustrate how cumulative genomic burden and borderline CNVs co-occur across different neurodevelopmental presentations, providing descriptive context for future mechanistic studies.