Structural mapping of GABRB3 variants reveals genotype–phenotype correlations

Katrine M. Johannesen, Sumaiya Iqbal, Milena Guazzi, Nazanin A. Mohammadi, Eduardo Pérez-Palma, Elise Schaefer, Anne De Saint Martin, Marie Therese Abiwarde, Amy McTague, Roser Pons, Amelie Piton, Manju A. Kurian, Gautam Ambegaonkar, Helen Firth, Alba Sanchis-Juan, Marie Deprez, Katrien Jansen, Liesbeth De Waele, Eva H. Briltra, Nienke E. VerbeekMarjan van Kempen, Walid Fazeli, Pasquale Striano, Federico Zara, Gerhard Visser, Hilde M.H. Braakman, Martin Haeusler, Miriam Elbracht, Ulvi Vaher, Thomas Smol, Johannes R. Lemke, Konrad Platzer, Joanna Kennedy, Karl Martin Klein, Ping Yee Billie Au, Kimberly Smyth, Julie Kaplan, Morgan Thomas, Malin K. Dewenter, Argirios Dinopoulos, Arthur J. Campbell, Dennis Lal, Damien Lederer, Vivian W.Y. Liao, Philip K. Ahring, Rikke S. Møller, Elena Gardella*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


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 Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.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.

Original languageEnglish
JournalGenetics in Medicine
Issue number3
Pages (from-to)681-693
Publication statusPublished - Mar 2022


  • Epilepsy
  • GABA
  • GABRB3
  • Genetics
  • Mapping


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