6533b7defe1ef96bd1275c47

RESEARCH PRODUCT

Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

subject

description

AbstractPurposePathogenic 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genotype-phenotype correlations.MethodsThrough an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3 and we reviewed previously published cases.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 pointsPathogenic variants in GABRB3 cause a wide range of phenotypesMissense variants in the ECD have generalized epilepsy with later onset and non-severe IDMissense variants in the TMD have focal epilepsy with early onset and severe IDBehavioral issues are common features of GABRB3 diseasePrecision medicine approaches for GABRB3 disease is limited