Clinical utility and genetic landscape of exome sequencing in a large pediatric epilepsy cohort: Insights from a Turkish tertiary care center.

OBJECTIVE

To evaluate the diagnostic utility and genetic spectrum of next-generation sequencing (NGS) in a large, well-phenotyped cohort of Turkish pediatric patients with epilepsy of unknown etiology.

METHODS

Between January 2021 and December 2024, 250 children (115 female, 135 male) with unexplained epilepsy underwent either whole-exome sequencing (WES; n = 104) or clinical exome sequencing (CES; n = 146). Variants were interpreted according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical data, including seizure semiology, neuroimaging, EEG findings, and treatment response, were retrospectively reviewed.

RESULTS

A definitive molecular diagnosis (pathogenic or likely pathogenic variants) was established in 89 patients (89/250, 35.6%). Including variants of uncertain significance (VUS) with strong phenotypic correlation raised the diagnostic yield to 57.6% (144/250). The genetic landscape was highly heterogeneous, involving 59 distinct genes. SCN1A was the most frequently implicated gene (n = 11, 12.4% of diagnosed cases), followed by MECP2 and PRRT2 (n = 5 each). Notably, the recurrent PRRT2 c.649dup (p.Arg217Profs*8) frameshift variant was identified in four unrelated Turkish families. Inheritance patterns included autosomal dominant (56/89, 63%), autosomal recessive (20/89, 22%), and X-linked (13/89, 15%). Diagnostic yields were comparable between WES (38/104, 36.5%) and CES (51/146, 35%) (p = 0.97). Neonatal-onset epilepsy (p = 0.03) and the presence of autistic features (p = 0.04) were significantly associated with a positive genetic diagnosis.

CONCLUSION

Our study confirms NGS as a first-tier diagnostic tool in pediatric epilepsy, revealing a distinctive genetic architecture enriched with novel and population-specific variants. These findings emphasize (1) a high diagnostic yield (∼36%) supporting first-tier use of NGS; (2) a distinctive genetic architecture characterized by recurrent PRRT2 variants and an elevated burden of autosomal recessive disorders, likely reflecting regional consanguinity patterns; and (3) a phenotype-driven framework for prioritizing VUS re-evaluation in clinical neurology practice. Such data from underrepresented populations are crucial for global genomic databases and directly inform precision medicine and genetic counseling.