Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

被引：11

作者：

Johannesen, Katrine M. ^{[1
,2
]}

Iqbal, Sumaiya ^{[3
,4
,5
]}

Guazzi, Milena ^{[6
,7
]}

Mohammadi, Nazanin A. ^{[1
,2
]}

Perez-Palma, Eduardo ^{[8
]}

Schaefer, Elise ^{[9
]}

De Saint Martin, Anne ^{[10
]}

Abiwarde, Marie Therese ^{[10
]}

McTague, Amy ^{[11
,12
]}

Pons, Roser ^{[13
]}

Piton, Amelie ^{[14
]}

Kurian, Manju A. ^{[11
,12
]}

Ambegaonkar, Gautam ^{[15
]}

Firth, Helen ^{[16
]}

Sanchis-Juan, Alba ^{[17
]}

Deprez, Marie ^{[18
]}

Jansen, Katrien ^{[19
]}

De Waele, Liesbeth ^{[19
,20
]}

Briltra, Eva H. ^{[21
]}

Verbeek, Nienke E. ^{[21
]}

van Kempen, Marjan ^{[21
]}

Fazeli, Walid ^{[22
]}

Striano, Pasquale ^{[23
,24
]}

Zara, Federico ^{[24
,25
]}

Visser, Gerhard ^{[26
]}

Braakman, Hilde M. H. ^{[27
,28
,29
]}

Haeusler, Martin ^{[30
]}

Elbracht, Miriam ^{[31
]}

Vaher, Ulvi ^{[32
,33
]}

Smol, Thomas ^{[34
]}

Lemke, Johannes R. ^{[35
]}

Platzer, Konrad ^{[35
]}

Kennedy, Joanna ^{[36
]}

Klein, Karl Martin ^{[37
,38
,39
,40
,41
,42
]}

Au, Ping Yee Billie ^{[43
]}

Smyth, Kimberly ^{[44
]}

Kaplan, Julie ^{[45
]}

Thomas, Morgan ^{[46
]}

Dewenter, Malin K. ^{[47
]}

Dinopoulos, Argirios ^{[48
]}

Campbell, Arthur J. ^{[3
,4
]}

Lal, Dennis ^{[4
,49
,50
,51
]}

Lederer, Damien ^{[52
]}

Liao, Vivian W. Y. ^{[53
]}

Ahring, Philip K. ^{[53
]}

Moller, Rikke S. ^{[1
,2
]}

Gardella, Elena ^{[1
,2
,6
,7
]}

机构：

[1] Danish Epilepsy Ctr Filadelfia, Dept Epilepsy Genet & Personalized Treatment, Dianalund, Denmark

[2] Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark

[3] Broad Inst MIT & Harvard, Ctr Dev Therapeut CDOT, Cambridge, MA 02142 USA

[4] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[5] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit ATGU, Boston, MA 02114 USA

[6] Univ Genoa, Dept Med, Genoa, Italy

[7] Danish Epilepsy Ctr Filadelfia, Dept Clin Neurophysiol, Dianalund, Denmark

[8] Univ Desarrollo, Fac Med Clin Alemana, Ctr Genet & Genom, Santiago, Chile

[9] Hop Univ Strasbourg, Inst Genet Med Alsace, Serv Genet Med, Strasbourg, France

[10] Strasbourg Univ Hosp, Dept Pediat Neurol, Strasbourg, France

[11] UCL Great Ormond St Inst Child Hlth, Dev Neurosci Programme, Mol Neurosci, London, England

[12] Great Ormond St Hosp Children NHS Fdn Trust, Dept Neurol, London, England

[13] Natl & Kapodistrian Univ Athens, I Agia Sofia Children Hosp, Dept Pediat 1, Athens, Greece

[14] CHRU Strasburg, Hop Civil, Lab Diagnost Genet, Strasbourg, France

[15] Addenbrookes Hosp, Child Dev Ctr, Dept Paediat Neurol, Cambridge, England

[16] Cambridge Univ Hosp NHS Fdn Trust, Dept Clin Genet, Cambridge, England

[17] Univ Cambridge, Dept Haematol, NIHR BioResource, Cambridge, England

[18] Univ Cote dAzur, IPMC, CNRS, Sophia Antipolis, France

[19] Univ Hosp KU Leuven, Dept Pediat Neurol, Leuven, Belgium

[20] Dept Dev & Regenerat, Kulak Kortrijk Campus, Kortrijk, Belgium

[21] Univ Utrecht, Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands

[22] Univ Hosp Bonn, Dept Pediat Neurol, Bonn, Germany

[23] IRCCS Giannina Gaslini Inst, Genoa, Italy

[24] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, Genoa, Italy

[25] IRCCS Giannina Gaslini Inst, Lab Neurogenet & Neurosci, Genoa, Italy

[26] Stichting Epilepsie Instellingen Nederland SEIN, Hoofddorp, Netherlands

[27] Radboud Univ Nijmegen Med Ctr, Amalia Childrens Hosp, Dept Pediat Neurol, Nijmegen, Netherlands

[28] Acad Ctr Epileptol Kempenhaeghe, Dept Neurol, Heeze, Netherlands

[29] Maastricht Univ Med Ctr, Heeze, Netherlands

[30] Univ Hosp RWTH Aachen, Dept Pediat, Div Neuropediat & Social Pediat, Aachen, Germany

[31] Rhein Westfal TH Aachen, Fac Med, Inst Human Genet, Aachen, Germany

[32] Tartu Univ Hosp, Childrens Clin, Tartu, Estonia

[33] ERN EpiCARE, Tartu, Estonia

[34] Univ Lille, CHU Lille, Inst Genet Med, Lille, France

[35] Univ Leipzig Med Ctr, Inst Human Genet, Leipzig, Germany

[36] Univ Hosp Bristol NHS Fdn Trust, Clin Genet Serv, St Michaels Hosp, Bristol, Avon, England

[37] Univ Calgary, Dept Clin Neurosci, Hotchkiss Brain Inst, Cumming Sch Med, Calgary, AB, Canada

[38] Univ Calgary, Alberta Childrens Hosp Res Inst, Cumming Sch Med, Calgary, AB, Canada

[39] Univ Calgary, Dept Med Genet, Hotchkiss Brain Inst, Cumming Sch Med, Calgary, AB, Canada

[40] Univ Calgary, Cumming Sch Med, Hotchkiss Brain Inst, Dept Community Hlth Sci, Calgary, AB, Canada

[41] Goethe Univ Frankfurt, Univ Hosp, Ctr Neurol & Neurosurg, Dept Neurol,Epilepsy Ctr Frankfurt Rhine Main, Frankfurt, Germany

[42] Goethe Univ Frankfurt, Ctr Personalized Translat Epilepsy Res CePTER, Frankfurt, Germany

[43] Univ Calgary, Cumming Sch Med, Alberta Childrens Hosp Res Inst, Dept Med Genet, Calgary, AB, Canada

[44] Univ Calgary, Cumming Sch Med, Dept Pediat, Calgary, AB, Canada

[45] Nemours AI DuPont Hosp Children, Div Med Genet, Wilmington, DE USA

[46] Nemours AI duPont Hosp Children, Precis Med Genet Testing Stewardship Program, Wilmington, DE USA

[47] Johannes Gutenberg Univ Mainz, Mainz Inst Humangenet, Inst Human Genet, Univ Med, Mainz, Germany

[48] Univ Athens, Attiko Univ Hosp, Dept Pediat 3, Haidari, Greece

[49] Cleveland Clin, Genom Med Inst, Lerner Res Inst, Cleveland, OH 44106 USA

[50] Cleveland Clin, Epilepsy Ctr, Neurol Inst, Cleveland, OH 44106 USA

来源：

GENETICS IN MEDICINE | 2022年 / 24卷 / 03期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

Epilepsy; GABA; GABRB3; Genetics; Mapping; DE-NOVO MUTATIONS; GABA(A) RECEPTOR; FEBRILE SEIZURES; ILAE COMMISSION; EPILEPSY; CLASSIFICATION; ONSET;

D O I：

10.1016/j.gim.2021.11.004

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：681 / 693

页数：13

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