Structural mapping of GABRB3 variants reveals genotype-phenotype correlations
Structural mapping of GABRB3 variants reveals genotype-phenotype correlations
Abstract PurposePathogenic 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. MethodsThrough an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3 and we reviewed previously published cases.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. ResultsWe 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. ConclusionThese 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 pointsPathogenic variants in GABRB3 cause a wide range of phenotypesMissense variants in the ECD have generalized epilepsy with later onset and non-severe IDMissense variants in the TMD have focal epilepsy with early onset and severe IDBehavioral issues are common features of GABRB3 diseasePrecision medicine approaches for GABRB3 disease is limited
McTague Amy、Lal Dennis、Johannesen Katrine M、Mohammadi Nazanin A、Abiwarde Marie Therese、Deprez Marie、Jansen Katrien、De Waele Liesbeth、Verbeek Nienke E、van Kempen Marjan、Fazeli Walid、Haeusler Martin、Platzer Konrad、Kennedy Joanna、Klein Karl Martin、Dewenter Malin K、Lederer Damien、Liao Vivian W Y、M?ller Rikke S.、Braakman Hilde M H、Pons Roser、Sanchis-Juan Alba、Kaplan Julie、Smyth Kimberly、Piton Amelie、Visser Gerhard、Guazzi Milena、Striano Pasquale、Iqbal Sumaiya、Campbell Arthur J、Schaefer Elise、Dinopoulos Argirios、Lemke Johannes R、Sternman David、P¨|rez-Palma Eduardo、Elbracht Miriam、Smol Thomas、De Saint Martin Anne、Firth Helen、Briltra Eva H、Thomas Morgan、Ahring Philip K、Ambegaonkar Gautam、Vaher Ulvi、Gardella Elena、Billie Au Ping Yee、Kurian Manju A、Zara Federico
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health||Department of Neurology, Great Ormond Street HospitalStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard||Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic||Epilepsy Center, Neurological Institute, Cleveland Clinic||Cologne Center for Genomics (CCG), University of CologneDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre||Department of Regional Health Research, University of Southern DenmarkDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre||Department of Regional Health Research, University of Southern DenmarkDepartment of Pediatric Neurology, Strasbourg University HospitalUniversit¨| C?te d?ˉAzurDepartment of Pediatric Neurology, University Hospitals LeuvenDepartment of Development and Regeneration, Campus Kulak Kortrijk||Department of Paediatric Neurology, University Hospitals LeuvenDepartment of Genetics, University Medical Center Utrecht, Utrecht UniversityDepartment of Genetics, University Medical Center Utrecht, Utrecht UniversityDepartment of Pediatric Neurology, University Hospital BonnDivision of Neuropediatrics and Social Pediatrics, Dept. of Pediatrics, University Hospital RWTH AachenInstitute of Human Genetics, University of Leipzig Medical CenterClinical Genetics Department, University Hospitals Bristol NHS Foundation Trust, St Michael?ˉs HospitalDepartments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children?ˉs Hospital Research Institute, Cumming School of Medicine, University of Calgary||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 FrankfurtInstitute of Human Genetics, Universit?tsmedizin, Johannes Gutenberg-University, Mainz Institut f¨1r HumangenetikCentre de G¨|n¨|tique Humaine, Institut de Pathologie et de G¨|n¨|tiqueBrain and Mind Centre, School of Pharmacy, Faculty of Medicine and Health, The University of SydneyDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre||Department of Regional Health Research, University of Southern DenmarkDepartment of Pediatric Neurology, Amalia Children?ˉs Hospital, Radboud University Medical Center||Department of Neurology, Academic Center for Epileptology Kempenhaeghe & Maastricht University Medical CenterFirst Department of Pediatrics, ?°I Agia Sofia?± Children Hospital, National & Kapodistrian University of AthensDepartment of Haematology, NIHR Bioresource, University of CambridgeDivision of Medical Genetics, Nemours A.I. duPont Hospital for ChildrenDepartment of Pediatrics, Cumming School of Medicine, University of CalgaryLaboratoire de diagnostic g¨|n¨|tique, H?pital CivilStichting Epilepsie Instellingen Nederland (SEIN)Department of Medicine, University of Genoa||Department of Clinical neurophysiology, the Danish Epilepsy CentreIRCCS Institute ?°Giannina Gaslini?±||Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of GenovaCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard||Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General HospitalCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardService de G¨|n¨|tique M¨|dicale, H?pitaux Universitaires de Strasbourg, Institut de G¨|n¨|tique M¨|dicale d?ˉAlsaceAttiko University Hospital, University of Athens, 3rd Dept of PediatricsInstitute of Human Genetics, University of Leipzig Medical CenterDivision of Neurology Lincoln Medical and Mental Health CenterUniversidad del Desarrollo, Centro de Gen¨|tica y Gen¨?mica, Facultad de Medicina Cl¨anica AlemanaInstitute of Human Genetics, Medical Faculty, RWTH Aachen UniversityInstitut de Genetique Medicale, CHRU Lille, Universite de LilleDepartment of Pediatric Neurology, Strasbourg University HospitalDepartment of Clinical Genetics, Cambridge University HospitalsDepartment of Genetics, University Medical Center Utrecht, Utrecht UniversityPrecision Medicine/Genetic Testing Stewardship Program, Nemours A.I. duPont Hospital for ChildrenBrain and Mind Centre, School of Pharmacy, Faculty of Medicine and Health, The University of SydneyDepartment of Paediatric Neurology, Child Development Centre, Addenbrookes HospitalChildren?ˉs Clinic of Tartu University Hospital||ERN EpiCAREDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre||Department of Regional Health Research, University of Southern Denmark||Department of Medicine, University of GenoaDepartment of Medical Genetics, Alberta Children?ˉs Hospital Research Institute, Cumming School of Medicine, University of CalgaryMolecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health||Department of Neurology, Great Ormond Street HospitalDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova||Laboratory of Neurogenetics and Neuroscience, IRCCS ?°G. Gaslini?± Institute
基础医学神经病学、精神病学遗传学
EpilepsyGeneticsGABAGABRB3mapping
McTague Amy,Lal Dennis,Johannesen Katrine M,Mohammadi Nazanin A,Abiwarde Marie Therese,Deprez Marie,Jansen Katrien,De Waele Liesbeth,Verbeek Nienke E,van Kempen Marjan,Fazeli Walid,Haeusler Martin,Platzer Konrad,Kennedy Joanna,Klein Karl Martin,Dewenter Malin K,Lederer Damien,Liao Vivian W Y,M?ller Rikke S.,Braakman Hilde M H,Pons Roser,Sanchis-Juan Alba,Kaplan Julie,Smyth Kimberly,Piton Amelie,Visser Gerhard,Guazzi Milena,Striano Pasquale,Iqbal Sumaiya,Campbell Arthur J,Schaefer Elise,Dinopoulos Argirios,Lemke Johannes R,Sternman David,P¨|rez-Palma Eduardo,Elbracht Miriam,Smol Thomas,De Saint Martin Anne,Firth Helen,Briltra Eva H,Thomas Morgan,Ahring Philip K,Ambegaonkar Gautam,Vaher Ulvi,Gardella Elena,Billie Au Ping Yee,Kurian Manju A,Zara Federico.Structural mapping of GABRB3 variants reveals genotype-phenotype correlations[EB/OL].(2025-03-28)[2025-05-08].https://www.medrxiv.org/content/10.1101/2021.06.04.21256727.点此复制
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