Expanding Insights into KCTD7-Related Drug-Resistant Epilepsy: Three Novel Mutations in a Cohort of Iranian Pediatric Patients.

Abstract

KCTD7-related epilepsy is a rare neurogenetic disorder characterized by marked genetic and phenotypic heterogeneity, typically presenting with early onset and often exhibiting poor response to conventional antiseizure medications. We performed exome sequencing in 134 Iranian pediatric patients with drug-resistant epilepsy and selected mutations in the KCTD7 gene. The pathogenicity of the identified variants was assessed using multiple in silico prediction tools and classified according to the ACMG guidelines. Additionally, we reviewed the genotype-phenotype correlations and treatment histories of all reported cases with KCTD7 mutations. Three novel homozygous variants-c.14C>T (p.Thr5Met), c.840delC (p.Ile281Serfs*11), and c.746T>G (p.Val249Gly)-were identified in four patients. Significant phenotypic heterogeneity was observed among patients, with disease severity ranging from mild to profound. Independent in silico analyses of each variant yielded concordant results, consistently predicting their potential to impact the structure and function of the KCTD7 protein. To date, 72 patients from 55 families have been reported, including 26.66% of homozygous cases born to non-consanguineous parents, and 37% of reported variants localized within BTB domain. Although 88.9% of patients experienced seizure onset before age two, clinical trajectories were highly variable. Among 45 patients with treatment data, valproate, levetiracetam, and clonazepam were the most frequently prescribed antiseizure medications; however, seizure control remained inconsistent. Notably, we observed subfertility in two heterozygous fathers, an unexpected finding that may suggest a potential role for KCTD7 beyond the central nervous system. These findings expand the mutational and phenotypic landscape of KCTD7-related epilepsy and underscore its clinical heterogeneity and therapeutic challenges.