Objawy i cechy genetyczne epilepsji związane z wariantami genu receptora GABAA: Charakterystyka genetyczna i kliniczna sześciu dzieci w Chinach
Phenotype and genotype of people with epilepsy and GABAA receptor gene variants: Genetic and clinical characterization of six children in China
W skrócie
Badacze przeanalizowali przypadki sześciu dzieci z epilepsją, które mają mutacje w genach odpowiedzialnych za produkcję receptorów GABA w mózgu. Odkryli, że te mutacje powodują różne formy epilepsji - u czterech dzieci prowadzą do zaburzeń rozwojowych, a u dwojga do padaczki z gorączkowymi napadami drgawek. Większość dzieci dobrze reaguje na leki, chociaż u jednego dziecka epilepsja okazała się odporna na standardowe leczenie.
Oryginalny abstract (angielski)
BACKGROUND: Variants in GABA-receptor subunits genes are linked to neurodevelopmental disorders and epilepsy, but genotype-phenotype correlations remain unclear. This study aims to describe the clinical characteristics of children with epilepsy harboring such variants and explore these correlations. METHODS: Trio-WES/WES results from 886 individuals with unexplained epilepsy, evaluated between January 2018 and December 2023, were reviewed. Six patients with pathogenic or likely pathogenic variants in GABA-receptor subunit genes (GABRA1, GABRG2) were included. Clinical phenotype, treatment, and genotype were analyzed. RESULTS: Four GABRA1 and two GABRG2 variants were identified in six unrelated families. Three variants (GABRA1 p.R159G, GABRG2 p.G273X, and GABRG2 p.R446Lfs*10) were novel. Computational predictions suggested these variants alter protein structure and impair receptor function. Clinically, four patients had developmental and epileptic encephalopathy and two had genetic epilepsy with febrile seizures plus. One patient had drug-resistant epilepsy, while the other five achieved stable seizure control with treatment,most commonly with valproate and levetiracetam. CONCLUSION: Clinical phenotypic heterogeneity in epilepsy associated with GABA receptor variants is significant and may relate to variant type and location. This study expands the spectrum of known pathogenic variants in a Chineses cohort and provides a reference for clinical diagnosis and genetic counseling. The findings underscore the need for large-scale collaborative studies to further refine genotype-phenotype correlations.