Whole-exome sequencing in a Turkish autism spectrum disorder cohort: a retrospective study of molecular diagnostic yield in isolated and complex presentations

Abstract Background Whole-exome sequencing (WES) can identify molecular etiologies in autism spectrum disorder (ASD), particularly when ASD occurs with developmental delay/intellectual disability (DD/ID), epilepsy, dysmorphism, congenital anomalies, or neuroimaging abnormalities. Data on WES yield and candidate-gene findings in Turkish ASD cohorts remain limited. We assessed molecular diagnostic yield and variant spectrum in a Turkish clinical ASD cohort, with comparison of isolated and complex ASD presentations. Methods This retrospective cohort study included 320 individuals with ASD evaluated by WES between 2020 and 2025. Patients were classified as having isolated or complex ASD based on co-occurring neurodevelopmental, neurological, dysmorphic, congenital, or systemic findings. Variants were interpreted using ACMG/AMP criteria. Established molecular diagnoses required pathogenic or likely pathogenic (P/LP) variants associated with OMIM-defined disorders or occurring in genes with definitive, strong, or moderate ClinGen evidence for a neurodevelopmental disorder (NDD). Categorical comparisons used two-sided Fisher’s exact test. Results Established molecular diagnoses were identified in 104/320 patients (32.5%; 95% confidence interval [CI], 27.4–37.9%), including 2/22 patients with isolated ASD (9.1%; 95% CI, 1.1–29.2%) and 102/298 patients with complex ASD (34.2%; 95% CI, 28.9–39.9%; p = 0.017). An additional 12 patients had P/LP variants in candidate or emerging genes, resulting in an overall P/LP finding rate of 116/320 (36.3%; 95% CI, 31.0–41.8%). Variants of uncertain significance were identified in 147 patients, while no ASD/NDD-related variant was identified in 57 patients. Conclusions WES supports etiological clarification in clinically complex ASD. Established molecular diagnoses were substantially more frequent in complex than isolated ASD. Candidate and emerging gene findings should be reported separately and interpreted as hypothesis-generating.