Genotype-phenotype correlations in KCNA2 related neurodevelopmental disorder: expanding the clinical and molecular...

Pathogenic variants in KCNA2 are associated with developmental and epileptic encephalopathy 32 (DEE32), but genotype-phenotype correlations remain unclear.

Whole-exome sequencing was performed in patients with developmental delay and/or epilepsy. Previously reported KCNA2 variants were reviewed to assess pathogenicity and genotype-phenotype associations. Structural modeling, in silico prediction, and spatiotemporal expression analyses were conducted to evaluate the potential effects of variants.

Four patients from unrelated families were identified with KCNA2 missense variants, including two novel variants, c.749T>G (p.Phe250Cys) and c.986G>A (p.Gly329Asp), and the recurrent variant c.1214C>T (p.Pro405Leu) in two patients. All patients presented with seizures, with or without mild developmental delay. Integrated analysis suggested that loss-of-function (LOF) variants were more likely to alter hydrophobicity, hydrogen bonding, and protein stability, and showed higher AlphaMissense scores, whereas gain-of-function (GOF) and mixed-function variants appeared less structurally damaging. Literature review showed that seizure onset was mostly in infancy or early childhood, consistent with the developmental expression pattern of KCNA2. LOF variants were generally associated with absent or mild developmental delay, while GOF and mixed-function variants were more frequently linked to severe developmental impairment.

This study expands the KCNA2 variant spectrum and supports a potential association between variant functional class and clinical severity. Integrating clinical data, structural modeling, and developmental expression analysis may improve understanding of KCNA2-related epilepsy and neurodevelopmental disorders.