Abstract
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 Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Genetics in Medicine |
| Vol/bind | 24 |
| Udgave nummer | 3 |
| Sider (fra-til) | 681-693 |
| ISSN | 1098-3600 |
| DOI | |
| Status | Udgivet - mar. 2022 |
Bibliografisk note
Funding Information:We thank the individuals and their families for participating in this study. A.M. and M.A.K. are partly funded by the NIHR Great Ormond Street Hospital Biomedical Research Centre. A.M. is funded by UK Regenerative Medicine Platform (MRC) and the Rosetrees Trust. The views expressed are those of the author(s) and not necessarily those of the The National Institute for Health Research (NHS), the National Institute for Health Research (NIHR), or the Department of Health. The Cambridge NIHR Bioresource provided support in this study. The Deciphering Developmental Disorders (DDD) study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee (REC) approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the NIHR, through the Comprehensive Clinical Research Network. This work was supported by Novo Nordisk Foundation (NNF19OC0058749 to R.S.M.), Lundbeck Foundation (R324-2019-1083 to R.S.M.), the Agencia Nacional de Investigaci?n y Desarrollo (ANID, PAI77200124 to E.P.) of Chile, and the FamilieSCN2A Foundation 2020 Action Potential Grant (to E.P.). P.S. worked within the framework of the Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno-infantili (DINOGMI) Department of Excellence of Ministero dell'IstruzioneMinistero dell'Universit? e della Ricerca (MIUR) 2018-2022 (legge 232 del 2016). Conceptualization: K.M.J. S.I. M.G. P.K.A. R.S.M. E.G.; Data Curation: K.M.J. S.I. M.G. N.A.M. E.P.-P. E.S. A.D.S.M. M.T.A. A.M. R.P. A.P. M.A.K. G.A. H.F. A.S.-J. M.D. K.J. L.D.W. E.H.B. N.E.V. M.v.K. W.F. G.V. P.S. F.Z. H.M.H.B. M.H. M.E. D.S. U.V. T.S. J.R.L. K.P. J.Ke. K.M.K. P.Y.B.A. K.S. J.Ka. M.T. M.K.D. A.D. D.La. D.Le. A.J.C. V.W.Y.L. P.K.A. R.S.M. E.G.; Formal Analysis: K.M.J. S.I. M.G. E.G.; Funding Acquisition: P.K.A. R.S.M.; Investigation: K.M.J. S.I. M.G. E.G.; Methodology: K.M.J. S.I. M.G. N.A.M. A.J.C. V.W.Y.L. P.K.A. R.S.M. E.G.; Supervision: D.La. P.S. A.J.C. P.K.A. R.S.M. E.G.; Visualization: K.M.J. S.I.; Writing-original draft: K.M.J. S.I. M.G. E.G.; Writing-review and editing: K.M.J. S.I. M.G. N.A.M. E.P.-P. E.S. A.D.S.M. M.T.A. A.M. R.P. A.P. M.A.K. M.D. K.J. L.D.W. E.H.B. N.E.V. M.v.K. W.F. G.V. H.M.H.B. P.S. F.Z. M.H. M.E. D.S. U.V. T.S. J.R.L. K.P. J.Ke. K.M.K. P.Y.B.A. P.S. K.S. J.Ka. M.T. M.D. A.D. D.La. D.Le. A.J.C. V.W.Y.L. P.K.A. R.S.M. E.G. All institutions involved in human participant research received local Institutional Review Board approval (main IRB: The ethics committee of Region Zealand, Denmark). Written informed consent, including authorization for reproduction of video images, was obtained for all individuals (or legal guardians) and family members where necessary. Individual data were collected according to local ethics committee guidelines.
Funding Information:
A.M. and M.A.K. are partly funded by the NIHR Great Ormond Street Hospital Biomedical Research Centre . A.M. is funded by UK Regenerative Medicine Platform (MRC) and the Rosetrees Trust. The views expressed are those of the author(s) and not necessarily those of the The National Institute for Health Research (NHS), the National Institute for Health Research (NIHR), or the Department of Health. The Cambridge NIHR Bioresource provided support in this study. The Deciphering Developmental Disorders (DDD) study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee (REC) approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the NIHR, through the Comprehensive Clinical Research Network.
Funding Information:
This work was supported by Novo Nordisk Foundation ( NNF19OC0058749 to R.S.M.), Lundbeck Foundation (R324-2019-1083 to R.S.M.), the Agencia Nacional de Investigación y Desarrollo (ANID, PAI77200124 to E.P.) of Chile, and the FamilieSCN2A Foundation 2020 Action Potential Grant (to E.P.). P.S. worked within the framework of the Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno-infantili (DINOGMI) Department of Excellence of Ministero dell'IstruzioneMinistero dell'Università e della Ricerca (MIUR) 2018-2022 (legge 232 del 2016).
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