Published 2022
| Version v1
Publication
Structural mapping of GABRB3 variants reveals genotype–phenotype correlations
Creators
- Johannesen K. M.
- Iqbal S.
- Guazzi M.
- Mohammadi N. A.
- Perez-Palma E.
- Schaefer E.
- De Saint Martin A.
- Abiwarde M. T.
- McTague A.
- Pons R.
- Piton A.
- Kurian M. A.
- Ambegaonkar G.
- Firth H.
- Sanchis-Juan A.
- Deprez M.
- Jansen K.
- De Waele L.
- Briltra E. H.
- Verbeek N. E.
- van Kempen M.
- Fazeli W.
- Striano P.
- Zara F.
- Visser G.
- Braakman H. M. H.
- Haeusler M.
- Elbracht M.
- Vaher U.
- Smol T.
- Lemke J. R.
- Platzer K.
- Kennedy J.
- Klein K. M.
- Au P. Y. B.
- Smyth K.
- Kaplan J.
- Thomas M.
- Dewenter M. K.
- Dinopoulos A.
- Campbell A. J.
- Lal D.
- Lederer D.
- Liao V. W. Y.
- Ahring P. K.
- Moller R. S.
- Gardella E.
Contributors
Others:
- Johannesen, K. M.
- Iqbal, S.
- Guazzi, M.
- Mohammadi, N. A.
- Perez-Palma, E.
- Schaefer, E.
- De Saint Martin, A.
- Abiwarde, M. T.
- Mctague, A.
- Pons, R.
- Piton, A.
- Kurian, M. A.
- Ambegaonkar, G.
- Firth, H.
- Sanchis-Juan, A.
- Deprez, M.
- Jansen, K.
- De Waele, L.
- Briltra, E. H.
- Verbeek, N. E.
- van Kempen, M.
- Fazeli, W.
- Striano, P.
- Zara, F.
- Visser, G.
- Braakman, H. M. H.
- Haeusler, M.
- Elbracht, M.
- Vaher, U.
- Smol, T.
- Lemke, J. R.
- Platzer, K.
- Kennedy, J.
- Klein, K. M.
- Au, P. Y. B.
- Smyth, K.
- Kaplan, J.
- Thomas, M.
- Dewenter, M. K.
- Dinopoulos, A.
- Campbell, A. J.
- Lal, D.
- Lederer, D.
- Liao, V. W. Y.
- Ahring, P. K.
- Moller, R. S.
- Gardella, E.
Description
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 Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.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.
Additional details
Identifiers
- URL
- http://hdl.handle.net/11567/1080620
- URN
- urn:oai:iris.unige.it:11567/1080620
Origin repository
- Origin repository
- UNIGE