Population-specific variant spectrum and epilepsy outcomes in IQSEC2-related neurodevelopmental disorder: a Chinese pediatric cohort

Background and Objectives: IQSEC2-related neurodevelopmental disorder is an X-linked condition characterized by developmental delay and epilepsy, with substantial phenotypic heterogeneity. Although sex-dependent clinical differences have been reported in western population, the population-specific genetic architecture and epilepsy treatment outcomes of IQSEC2 -related disorder remain incompletely characterized, particularly in East Asian populations. This study aims to delineate the clinical features, variant spectrum and epilepsy outcomes in a Chinese pediatric cohort with IQSEC2 -associated disorders. Methods We retrospectively analyzed the clinical manifestations, genetic findings, antiseizure medication use, and follow-up outcomes of 35 Chinese children with potential disease causing by variants in IQSEC2. Variants were identified by WES and classified according to ACMG/AMP guidelines, with additional analysis of variant inheritance and intragenic copy-number variants. Results The cohort included 20 males and 15 females, with symptom onset predominantly between 1 and 7 years of age. Females were diagnosed at a significantly later age than males (Mann-Whitney U test, P = 0.0161). All patients exhibited developmental delay, and epilepsy was observed in 17 of 35 individuals (48.57%), with a high proportion of refractory epilepsy 47.05% (8/17). Females generally demonstrated milder epilepsy phenotypes and more favorable seizure control compared with males, including higher rates of seizure freedom at follow-up. Genetic analysis identified a distinct variant spectrum, with a predominance of truncating variants, and one intragenic exon 5–9 deletion, of which 68.57% were de novo , highlighting population-specific differences from previously reported Western cohorts. Among patients with epilepsy, seizure control was achieved in ten individuals during follow-up, with substantial variability in response to antiseizure medications. Conclusions This Chinese cohort study delineates the clinical and genetic spectrum of disease in the IQSEC2 -related X-linked intellectual disability population, revealing notable sex-related differences in disease manifestation.