Structural mapping of GABRB3 variants reveals genotype-phenotype correlation

Abstract

PurposePathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability. In the present study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. MethodsThrough an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3 and we reviewed previously published cases. All missense variants were mapped onto the 3D structure of the GABRB3 subunit and clinical phenotypes associated with the different key structural domains were investigated. ResultsWe characterize 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 10.5 months, and mild-to-moderate intellectual disability were associated with variants in the extracellular domain. Focal epilepsy with early onset (median: 2.75 months of age) and severe intellectual disability were associated with variants in the pore-lining helical transmembrane domain. ConclusionThese genotype/phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences. Key pointsO_LIPathogenic variants in GABRB3 cause a wide range of phenotypes C_LIO_LIMissense variants in the ECD have generalized epilepsy with later onset and non-severe ID C_LIO_LIMissense variants in the TMD have focal epilepsy with early onset and severe ID C_LIO_LIBehavioral issues are common features of GABRB3 disease C_LIO_LIPrecision medicine approaches for GABRB3 disease is limited C_LI