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 af dette arbejde

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METHODS: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.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

Sider (fra-til)681-693
Antal sider13
TidsskriftGenetics in Medicine
Udgave nummer3
Tidlig onlinedato7 dec. 2021
StatusUdgivet - mar. 2022

Bibliografisk note

Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.


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