Structural Variant and Repeat Expansion Findings Identified by Optical Genome Mapping in Complex Autism Spectrum...

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction, along with restricted, repetitive patterns of behavior, interests, or activities. Single-nucleotide variants (SNVs) and structural variants (SVs), including copy-number variants (CNVs), have been reported as important contributors to the genetic basis of ASD. In this study, we evaluated the diagnostic contribution of optical genome mapping (OGM) as a complementary cytogenomic approach in a selected ASD cohort enriched for complex ASD with developmental delay/intellectual disability (DD/ID) and/or additional neurodevelopmental or syndromic features. We retrospectively evaluated 34 individuals with ASD who underwent OGM analysis, most of whom had concomitant DD/ID and/or additional neurological, congenital, or syndromic features. Confirmed pathogenic (P) or likely pathogenic (LP) findings were identified in 7/34 individuals (20.6%), and one additional unconfirmed OGM-only duplication was provisionally interpreted as pathogenic. Overall, confirmed or provisional P/LP findings were observed in 8/34 individuals (23.5%), all of whom had complex ASD with DD/ID and/or additional neurodevelopmental or syndromic features. OGM-detected findings were confirmed by orthogonal methods whenever clinically and technically feasible, and segregation analyses were performed when samples were available. These results suggest that OGM may add value to integrated genetic testing workflows for selected individuals with complex ASD, particularly when SVs, complex chromosomal rearrangements, or FMR1 full-mutation repeat expansions are clinically suspected or insufficiently resolved by conventional approaches.