Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

Genet Med. 2022 Mar;24(3):681-693. doi: 10.1016/j.gim.2021.11.004. Epub 2021 Dec 7.


Purpose: Pathogenic 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 (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations.

Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.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 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated.

Results: We characterized 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 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain.

Conclusion: These 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.

Keywords: Epilepsy; GABA; GABRB3; Genetics; Mapping.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Epilepsy* / genetics
  • Genetic Association Studies
  • Humans
  • Intellectual Disability* / genetics
  • Mutation
  • Phenotype
  • Receptors, GABA-A / genetics


  • GABRB3 protein, human
  • Receptors, GABA-A