Diagnostic Yield of Whole Exome Sequencing in Autism Spectrum Disorder Patients at a Tertiary Center in Saudi Arabia.

PURPOSE: Autism spectrum disorder (ASD) is a clinically and genetically heterogeneous neurodevelopmental condition. Whole‑exome sequencing (WES) is a pivotal diagnostic tool, though its yield varies across populations. This study aimed to determine the diagnostic yield and characterize the genetic spectrum identified by WES in a pediatric ASD cohort from Saudi Arabia.

METHODS

We conducted a retrospective cohort study of 288 children (< 14 years) with DSM‑5‑confirmed ASD who underwent clinical WES at a tertiary center between 2021 and 2024. Variants were classified according to ACMG/AMP guidelines.

RESULTS

The overall diagnostic yield for pathogenic or likely pathogenic variants was 30% (86/288). Variants of uncertain significance were identified in 22% (63/288) of patients. Recurrently affected genes included SHANK3, SCN2A, SYNGAP1, CAMK2A, GRIN2B, and CNTNAP2. Notably, variants in GFAP, a gene primarily associated with Alexander disease, were found in six patients presenting with ASD, macrocephaly, and developmental delay.

CONCLUSIONS

WES provided a molecular diagnosis in 30% of this Saudi ASD cohort. The identification of GFAP variants raises the hypothesis that astrocytic dysfunction may play a role in a subset of ASD cases, though this finding requires independent replication and functional validation. These results underscore the clinical utility of WES and highlight the need for population‑specific genomic resources.