STXBP1 Variants Associated With Epilepsy With Variable Severity
TL;DR
Clinical severity broadly tracks with the predicted structural/biophysical impact of the variant and Munc18‐1 abundance, providing a mechanistic clue for phenotypic heterogeneity in STXBP1‐related disorders.
Abstract
ABSTRACT Introduction Pathogenic variants in STXBP1 are a well‐established cause of developmental and epileptic encephalopathy (DEE), whereas their contribution to milder epilepsy phenotypes remains under‐characterized. We sought to delineate STXBP1 variants across a clinical severity spectrum and to explore molecular correlates of phenotypic heterogeneity. Methods Trio‐based whole‐exome sequencing was performed in patients with unexplained epilepsy recruited from multiple epilepsy centers. Variants were confirmed by Sanger sequencing and interpreted using ACMG criteria. Missense variants were assessed using structural modeling and biophysical prediction tools, and their effects on Munc18‐1 expression were evaluated by immunoblotting in transfected HEK293T cells. Results Eight STXBP1 variants were identified in eight unrelated cases, including one truncating variant (Lys63Ter) and seven missense variants. Five de novo missense variants (Pro187Leu, Arg190Gln, Ala251Thr, Arg292His, and Gly544Val) and one de novo truncating variant were observed exclusively in individuals with DEE. In contrast, Gly236Val segregated in a family with epilepsy with febrile seizures plus, and Pro434Leu was inherited in a family with self‐limited epilepsy with centrotemporal spikes with incomplete penetrance. In silico analyses suggested that Gly236Val and Pro434Leu had comparatively milder destabilizing effects and were located at more solvent‐accessible positions than DEE‐associated variants. Consistently, immunoblotting showed markedly reduced Munc18‐1 levels for DEE‐associated missense variants, whereas Gly236Val and Pro434Leu preserved similar Munc18‐1 levels to wild‐type expression. Conclusions STXBP1 variants may underlie epilepsies of variable severity, extending from milder epilepsy syndromes to DEE. Clinical severity broadly tracks with the predicted structural/biophysical impact of the variant and Munc18‐1 abundance, providing a mechanistic clue for phenotypic heterogeneity in STXBP1‐related disorders.