Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variantsResearch in context
Nazanin Azarinejad Mohammadi,
Philip Kiær Ahring,
Vivian Wan Yu Liao,
Han Chow Chua,
Sebastián Ortiz de la Rosa,
Katrine Marie Johannesen,
Yael Michaeli-Yossef,
Aline Vincent-Devulder,
Catherine Meridda,
Ange-Line Bruel,
Alessandra Rossi,
Chirag Patel,
Joerg Klepper,
Paolo Bonanni,
Sara Minghetti,
Marina Trivisano,
Nicola Specchio,
David Amor,
Stéphane Auvin,
Sarah Baer,
Pierre Meyer,
Mathieu Milh,
Vincenzo Salpietro,
Reza Maroofian,
Johannes R. Lemke,
Sarah Weckhuysen,
Palle Christophersen,
Guido Rubboli,
Mary Chebib,
Anders A. Jensen,
Nathan L. Absalom,
Rikke Steensbjerre Møller
Affiliations
Nazanin Azarinejad Mohammadi
Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Philip Kiær Ahring
School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
Vivian Wan Yu Liao
School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
Han Chow Chua
Sydney Pharmacy School, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
Sebastián Ortiz de la Rosa
Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Katrine Marie Johannesen
Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
Yael Michaeli-Yossef
Pediatric Neurology Unit and Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel
Aline Vincent-Devulder
Genetic Department, CHU Côte de Nacre, Caen, France
Catherine Meridda
Genetic Department, CHU Côte de Nacre, Caen, France
Ange-Line Bruel
Genetic Department, CHU Côte de Nacre, Caen, France
Alessandra Rossi
Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Pediatric Clinic, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
Chirag Patel
Genetic Health Queensland, Royal Brisbane & Women’s Hospital, Brisbane, QLD 4029, Australia
IRCCS E. Medea Scientific Institute, Epilepsy Unit, Conegliano, Treviso, Italy
Sara Minghetti
IRCCS E. Medea Scientific Institute, Clinical Neurophysiology Unit, Bosisio Parini, LC, Italy
Marina Trivisano
Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy
Nicola Specchio
Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy
David Amor
Murdoch Children’s Research Institute, Melbourne, Australia
Stéphane Auvin
Université de Paris, Child Neurology & Epilepsy, Paris, France; Robert-Debré Hospital, Center for Rare Epilepsies - Pediatric Neurology, Paris, France
Sarah Baer
Department of Paediatric Neurology, French Reference Center of Rare Epilepsies CREER, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Pierre Meyer
Paediatric Neurology Department, Phymedexp, Montpellier University, Inserm, CNRS, University Hospital Montpellier, Montpellier, France
Mathieu Milh
Department of Pediatric Neurology, AP-HM, La Timone Children's Hospital, Marseille, France; Faculté de Médecine Timone, Aix Marseille Univ, INSERM, MMG, U1251, ERN EpiCARE, Marseille, France
Vincenzo Salpietro
Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, Genoa, Italy
Reza Maroofian
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK
Johannes R. Lemke
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany; Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany
Sarah Weckhuysen
Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Antwerp, Belgium; Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium
Palle Christophersen
Saniona A/S, Ballerup, Denmark
Guido Rubboli
Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Mary Chebib
School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
Anders A. Jensen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Nathan L. Absalom
School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; School of Science, Western Sydney University, Sydney, Australia; Corresponding author. School of Science, Western Sydney University, New South Wales 2751, Australia.
Rikke Steensbjerre Møller
Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; Corresponding author. Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark.
Summary: Background: Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) 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 α1β2γ2 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 flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. Funding: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.
