Diagnostic Yield and Genotype–Phenotype Overlap in Pediatric Autism Spectrum Disorder Patients Using Whole-Exome Sequencing and Phenotype-Driven Variant Interpretation: A Single-Center Cohort Study

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Background/Objectives: Autism spectrum disorder (ASD) is a clinically and genetically heterogeneous neurodevelopmental condition, and the diagnostic yield of whole-exome sequencing (WES) varies across settings. This single-center study aimed to determine the molecular diagnostic yield of WES in pediatric ASD and to explore genotype–phenotype overlap using a structured, phenotype-driven reanalysis strategy. Methods: We enrolled 60 children with syndromic and non-syndromic ASD, who underwent detailed clinical and dysmorphology assessment. WES for single-nucleotide and copy-number variant (CNV) detection was performed in an accredited laboratory, followed by clinician-driven reinterpretation, integrating expanded phenotypic data and ACMG/AMP-based variant classification. Genes were considered if they harbored rare, potentially pathogenic variants and were previously reported or curated in established ASD-associated gene resources. Results: The initial external laboratory report identified 5 of 60 patients (8.3%) with a pathogenic (P) or likely pathogenic (LP) variant (positive result), 30 of 60 (50.0%) with a variant of unknown significance (VUS) (inconclusive result), and 25 of 60 (41.7%) with a negative result. Clinician-based variant reinterpretation identified pathogenic or likely pathogenic variants in 9 of 60 patients (15.0%), representing an 80% relative increase in diagnostic yield, as well as 43 VUSs distributed across 34 patients, while 17 patients had no reportable variants (negative result). Overall, reanalysis revealed 11 additional variants of interest (pathogenic, likely pathogenic, or VUS) that had not been reported in the initial assessment. In total, 52 sequence and copy-number variants in 46 genes were detected, most of which were VUSs (83%). Conclusions: In this pediatric ASD cohort, WES with phenotype-driven reinterpretation and CNV assessment yielded a clinically positive result in 15% of patients and uncovered additional candidate variants, highlighting both the value and the current interpretative challenge of comprehensive genomic testing in ASD.

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