Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants

被引：2

作者：

Mohammadi, Nazanin Azarinejad ^{[1
,2
]}

Ahring, Philip Kiaer ^{[3
]}

Liao, Vivian Wan Yu ^{[3
]}

Chua, Han Chow ^{[4
]}

Rosa, Sebastian Ortiz de la ^{[1
,2
]}

Johannesen, Katrine Marie ^{[1
,5
]}

Michaeli-Yossef, Yael ^{[6
,7
]}

Vincent-Devulder, Aline ^{[8
]}

Meridda, Catherine ^{[8
]}

Bruel, Ange-Line ^{[8
]}

Rossi, Alessandra ^{[1
,9
]}

Patel, Chirag ^{[10
]}

Klepper, Joerg ^{[11
]}

Bonanni, Paolo ^{[12
]}

Minghetti, Sara ^{[13
]}

Trivisano, Marina ^{[14
]}

Specchio, Nicola ^{[14
]}

Amor, David ^{[15
]}

Auvin, Stephane ^{[16
,17
]}

Baer, Sarah ^{[18
]}

Meyer, Pierre ^{[19
]}

Milh, Mathieu ^{[20
,21
]}

Salpietro, Vincenzo ^{[22
,23
]}

Maroo, Reza ^{[24
]}

Lemke, Johannes R. ^{[25
,26
]}

Weckhuysen, Sarah ^{[27
,28
,29
]}

Christophersen, Palle ^{[30
]}

Rubboli, Guido ^{[1
,31
]}

Chebib, Mary ^{[3
]}

Jensen, Anders A. ^{[32
]}

Absalom, Nathan L. ^{[3
,33
]}

Moller, Rikke Steensbjerre ^{[1
,2
]}

机构：

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

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

[3] Univ Sydney, Fac Med & Hlth, Brain & Mind Ctr, Sch Med Sci, Sydney, NSW 2006, Australia

[4] Univ Sydney, Fac Med & Hlth, Charles Perkins Ctr, Sydney Pharm Sch, Sydney, NSW 2006, Australia

[5] Univ Hosp Copenhagen, Dept Genet, Rigshospitalet, Copenhagen, Denmark

[6] Wolfson Med Ctr, Pediat Neurol Unit, Holon, Israel

[7] Wolfson Med Ctr, Metab Neurogenet Clin, Holon, Israel

[8] CHU Cote Nacre, Genet Dept, Caen, France

[9] Univ Pavia, IRCCS San Matteo Hosp Fdn, Pediat Clin, Pavia, Italy

[10] Royal Brisbane & Womens Hosp, Genet Hlth Queensland, Brisbane, Qld 4029, Australia

[11] Childrens Hosp Aschaffenburg Alzenau, Aschaffenburg, Germany

[12] IRCCS E Medea Sci Inst, Epilepsy Unit, Conegliano, Treviso, Italy

[13] IRCCS E Medea Sci Inst, Clin Neurophysiol Unit, Bosisio Parini, Italy

[14] Bambino Gesu Pediat Hosp, IRCCS, European Reference NetworkEpiCARE, Neurol Epilepsy & Movement Disorders, Rome, Italy

[15] Murdoch Childrens Res Inst, Melbourne, Australia

[16] Univ Paris, Child Neurol & Epilepsy, Paris, France

[17] Robert Debre Hosp, Ctr Rare Epilepsies Pediat Neurol, Paris, France

[18] Hop Univ Strasbourg, French Reference Ctr Rare Epilepsies CREER, Dept Paediat Neurol, Strasbourg, France

[19] Montpellier Univ, Univ Hosp Montpellier, Paediat Neurol Dept, Phymedexp,Inserm,CNRS, Montpellier, France

[20] Timone Childrens Hosp, AP HM, Dept Pediat Neurol, Marseille, France

[21] Aix Marseille Univ, Fac Med Timone, INSERM, MMG,U1251,ERN EpiCARE, Marseille, France

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

[23] IRCCS Giannina Gaslini Inst, Pediat Neurol & Muscular Dis Unit, Genoa, Italy

[24] UCL Queen Sq Inst Neurol, Dept Neuromusc Disorders, London, England

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

[26] Univ Leipzig, Ctr Rare Dis, Med Ctr, Leipzig, Germany

[27] VIB, VIB Ctr Mol Neurol, Appl & Translat Neurogenom Grp, Antwerp, Belgium

[28] Antwerp Univ Hosp, Dept Neurol, Antwerp, Belgium

[29] Univ Antwerp, Fac Med & Hlth Sci, Translat Neurosci, Antwerp, Belgium

[30] Saniona AS, Ballerup, Denmark

[31] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark

[32] Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Copenhagen, Denmark

[33] Western Sydney Univ, Sch Sci, Sydney, NSW 2751, Australia

来源：

EBIOMEDICINE | 2024年 / 106卷

基金：

英国医学研究理事会;

关键词：

GABA A receptors; Gain-of-function; Epilepsy; Seizures; Dystonia; Movement disorders; DE-NOVO MUTATIONS; GABA(A) RECEPTORS; MEDICAL GENETICS; VARIANTS; SEIZURES; SUBUNITS;

D O I：

10.1016/j.ebiom.2024.105236

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Variants in GABRB2 , encoding the 0 2 subunit of the gamma-aminobutyric acid type A (GABA(A) ) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype - phenotype correlation analysis in a cohort of individuals with GABRB2 variants. Methods Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Findings Electrophysiological assessments of alpha 1 0 2 gamma 2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. Interpretation The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic fl owchart that aids in predicting the pathogenicity of recently identi fi ed variants by considering clinical phenotypes.

引用

页数：20

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