Structural mapping of GABRB3 variants reveals genotype-phenotype correlations
Abstract
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. In the present 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 Methods Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3 and we reviewed previously published cases.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 3D structure of the GABRB3 subunit and clinical phenotypes associated with the different key structural domains were investigated. Results We characterize 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 10.5 months, and mild-to-moderate intellectual disability were associated with variants in the extracellular domain. Focal epilepsy with early onset (median: 2.75 months of age) and severe intellectual disability were associated with variants in the pore-lining helical transmembrane 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. Key points Pathogenic variants in GABRB3 cause a wide range of phenotypes Missense variants in the ECD have generalized epilepsy with later onset and non-severe ID Missense variants in the TMD have focal epilepsy with early onset and severe ID Behavioral issues are common features of GABRB3 disease Precision medicine approaches for GABRB3 disease is limited
Authors 47
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Katrine M. Johannesen corresponding
University of Southern Denmark
Affiliation as printed
Department of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre, Dianalund, Denmark
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
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Broad Institute · Massachusetts General Hospital · Stanley Center for Psychiatric Research
Affiliation as printed
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, USA
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA
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Affiliation as printed
Department of Clinical neurophysiology, the Danish Epilepsy Centre, Dianalund, Denmark
Department of Medicine, University of Genoa, Genoa, Italy
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University of Southern Denmark
Affiliation as printed
Department of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre, Dianalund, Denmark
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
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Universidad del Desarrollo · Clínica Alemana
Affiliation as printed
Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Santiago de Chile, Chile
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Hôpitaux Universitaires de Strasbourg
Affiliation as printed
Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d’Alsace, Strasbourg, France
Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d'Alsace, Strasbourg, France
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Hôpitaux Universitaires de Strasbourg
Affiliation as printed
Department of Pediatric Neurology, Strasbourg University Hospital, Strasbourg, France
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Hôpitaux Universitaires de Strasbourg
Affiliation as printed
Department of Pediatric Neurology, Strasbourg University Hospital, Strasbourg, France
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University College London · Great Ormond Street Hospital
Affiliation as printed
Department of Neurology, Great Ormond Street Hospital, London, United Kingdom
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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National and Kapodistrian University of Athens · Children's Hospital Agia Sophia
Affiliation as printed
First Department of Pediatrics, “I Agia Sofia” Children Hospital, National & Kapodistrian University of Athens, Athens, Greece
First Department of Pediatrics, "I Agia Sofia" Children Hospital, National & Kapodistrian University of Athens, Athens, Greece
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Affiliation as printed
Laboratoire de diagnostic génétique, Hôpital Civil, CHRU Strasbourg, Strasbourg, France
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University College London · Great Ormond Street Hospital
Affiliation as printed
Department of Neurology, Great Ormond Street Hospital, London, United Kingdom
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Affiliation as printed
Department of Paediatric Neurology, Child Development Centre, Addenbrookes Hospital, Cambridge, United Kingdom
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University of Cambridge · Cambridge University Hospitals NHS Foundation Trust
Affiliation as printed
Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, United Kingdom
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University of Cambridge · NIHR BioResource
Affiliation as printed
Department of Haematology, NIHR Bioresource, University of Cambridge, United Kingdom
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Centre National de la Recherche Scientifique · Université Côte d'Azur · Institut de Pharmacologie Moléculaire et Cellulaire
Affiliation as printed
Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France
Université Côte d'Azur, CNRS, IPMC, Sophia-Antipolis, France
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Pediatric Neurology, University Hospitals Leuven, Belgium
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Development and Regeneration, Campus Kulak Kortrijk, Kortrijk, Belgium
Department of Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium
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University Medical Center Utrecht · Utrecht University
Affiliation as printed
Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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University Medical Center Utrecht · Utrecht University
Affiliation as printed
Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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University Medical Center Utrecht · Utrecht University
Affiliation as printed
Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Affiliation as printed
Department of Pediatric Neurology, University Hospital Bonn, Bonn, Germany
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Istituto Giannina Gaslini · University of Genoa
Affiliation as printed
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
IRCCS Institute “Giannina Gaslini”, Genova, Italy
IRCCS Institute "Giannina Gaslini", Genova, Italy
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Istituto Giannina Gaslini · University of Genoa
Affiliation as printed
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
Laboratory of Neurogenetics and Neuroscience, IRCCS “G. Gaslini” Institute, Genova, Italy
Laboratory of Neurogenetics and Neuroscience, IRCCS "G. Gaslini" Institute, Genova, Italy
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Stichting Epilepsie Instellingen Nederland
Affiliation as printed
Stichting Epilepsie Instellingen Nederland (SEIN), Hoofddorp, The Netherlands
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Maastricht University · Radboud University Medical Center · Radboud University Nijmegen · Amalia Kinderziekenhuis · Maastricht University Medical Centre · Kempenhaeghe
Affiliation as printed
Department of Neurology, Academic Center for Epileptology Kempenhaeghe & Maastricht University Medical Center, Heeze, The Netherlands
Department of Pediatric Neurology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
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Martin C. H. Haeusler Aachen Department of Pediatrics Division of Neuropediatrics and Social Pediatrics
RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Division of Neuropediatrics and Social Pediatrics, Dept. of Pediatrics, University Hospital RWTH Aachen, Germany
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Division of Neurology Lincoln Medical and Mental Health Center, Bronx, NY, United States
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University of Tartu · Tartu University Hospital
Affiliation as printed
Children’s Clinic of Tartu University Hospital, Tartu, Estonia
ERN EpiCARE, Tartu, Estonia
Children's Clinic of Tartu University Hospital, Tartu, Estonia
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Université de Lille · Centre Hospitalier Universitaire de Lille
Affiliation as printed
Institut de Genetique Medicale, CHRU Lille, Universite de Lille, Lille, France
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University Hospital Leipzig · Leipzig University
Affiliation as printed
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
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University Hospital Leipzig · Leipzig University
Affiliation as printed
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
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St Michael's Hospital · University Hospitals Bristol NHS Foundation Trust
Affiliation as printed
Clinical Genetics Department, University Hospitals Bristol NHS Foundation Trust, St Michael’s Hospital, Bristol, United Kingdom
Clinical Genetics Department, University Hospitals Bristol NHS Foundation Trust, St Michael's Hospital, Bristol, United Kingdom
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University of Calgary · University Hospital Frankfurt · Goethe University Frankfurt · Hotchkiss Brain Institute · Alberta Children's Hospital Research Institute
Affiliation as printed
Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Germany and Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Germany
Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
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University of Calgary · Alberta Children's Hospital Research Institute
Affiliation as printed
Department of Medical Genetics, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
Department of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
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Affiliation as printed
Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Canada
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Alfred I. duPont Hospital for Children
Affiliation as printed
Division of Medical Genetics, Nemours A.I. duPont Hospital for Children, Wilmington, Delaware, USA
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Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz
Affiliation as printed
Institute of Human Genetics, Universitätsmedizin, Johannes Gutenberg-University, Mainz Institut für Humangenetik, Mainz, Germany
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National and Kapodistrian University of Athens
Affiliation as printed
Attiko University Hospital, University of Athens, 3rd Dept of Pediatrics, Haidari, Greece
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Broad Institute · Stanley Center for Psychiatric Research
Affiliation as printed
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, USA
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA
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Cleveland Clinic · University of Cologne · Broad Institute · Stanley Center for Psychiatric Research
Affiliation as printed
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA
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Institute of Pathology and Genetics
Affiliation as printed
Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Charleroi, Gosselies, Belgium
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Affiliation as printed
Brain and Mind Centre, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
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Affiliation as printed
Brain and Mind Centre, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
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University of Southern Denmark
Affiliation as printed
Department of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre, Dianalund, Denmark
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
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Elena Gardella corresponding
University of Genoa · University of Southern Denmark
Affiliation as printed
Department of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre, Dianalund, Denmark
Department of Medicine, University of Genoa, Genoa, Italy
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
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