Johannesen, Katrine M., Iqbal, Sumaiya, Guazzi, Milena, Mohammadi, Nazanin A., Perez-Palma, Eduardo, Schaefer, Elise, De Saint Martin, Anne, Abiwarde, Marie Therese, McTague, Amy, Pons, Roser, Piton, Amelie, Kurian, Manju A., Ambegaonkar, Gautam, Firth, Helen, Sanchis-Juan, Alba, Deprez, Marie, Jansen, Katrien, De Waele, Liesbeth, Briltra, Eva H., Verbeek, Nienke E., van Kempen, Marjan, Fazeli, Walid, Striano, Pasquale, Zara, Federico, Visser, Gerhard, Braakman, Hilde M. H., Haeusler, Martin, Elbracht, Miriam, Vaher, Ulvi, Smol, Thomas ORCID: 0000-0002-0119-5896, Lemke, Johannes R., Platzer, Konrad, Kennedy, Joanna, Klein, Karl Martin ORCID: 0000-0002-6654-1665, Au, Ping Yee Billie, Smyth, Kimberly, Kaplan, Julie, Thomas, Morgan, Dewenter, Malin K., Dinopoulos, Argirios, Campbell, Arthur J., Lal, Dennis, Lederer, Damien, Liao, Vivian W. Y., Ahring, Philip K., Moller, Rikke S. ORCID: 0000-0002-9664-1448 and Gardella, Elena (2022). Structural mapping of GABRB3 variants reveals genotype-phenotype correlations. Genet. Med., 24 (3). S. 681 - 694. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1530-0366

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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 Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.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. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Johannesen, Katrine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iqbal, SumaiyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guazzi, MilenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohammadi, Nazanin A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Palma, EduardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefer, EliseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Saint Martin, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abiwarde, Marie ThereseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McTague, AmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pons, RoserUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piton, AmelieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kurian, Manju A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ambegaonkar, GautamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Firth, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchis-Juan, AlbaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deprez, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jansen, KatrienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Waele, LiesbethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Briltra, Eva H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verbeek, Nienke E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Kempen, MarjanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fazeli, WalidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striano, PasqualeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zara, FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Visser, GerhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braakman, Hilde M. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haeusler, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elbracht, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaher, UlviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smol, ThomasUNSPECIFIEDorcid.org/0000-0002-0119-5896UNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Platzer, KonradUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kennedy, JoannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, Karl MartinUNSPECIFIEDorcid.org/0000-0002-6654-1665UNSPECIFIED
Au, Ping Yee BillieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smyth, KimberlyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaplan, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, MorganUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dewenter, Malin K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dinopoulos, ArgiriosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, Arthur J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lederer, DamienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liao, Vivian W. Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahring, Philip K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDorcid.org/0000-0002-9664-1448UNSPECIFIED
Gardella, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-698972
DOI: 10.1016/j.gim.2021.11.004
Journal or Publication Title: Genet. Med.
Volume: 24
Number: 3
Page Range: S. 681 - 694
Date: 2022
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DE-NOVO MUTATIONS; GABA(A) RECEPTOR; FEBRILE SEIZURES; ILAE COMMISSION; EPILEPSY; CLASSIFICATION; ONSETMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69897

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