ArticleGenetics in medicine : official journal of the American College of Medical Genetics2023
Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 10 citations in OpenAlex.
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- Abrupt and Severe Onset of Dystonia, Chorea and Hemiplegic Episodes in a Young Boy with a Novel Heterozygous Missense Variant in the GTPase Domain of RHOBTB2.Movement disorders clinical practice · 2025Article
- Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy.Human molecular genetics · 2025Article
- Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.Biomolecules · 2025Review
- RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant Analysis.Molecular genetics & genomic medicine · 2025Article
- Characterization of 13 Novel Genetic Variants in Genes Associated with Epilepsy: Implications for Targeted Therapeutic Strategies.Molecular diagnosis & therapy · 2024Article
- Variants inFrontiers in pediatrics · 2024Review
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Authors and funding
64 authors at 20 institutions in 16 countries.
Franziska LanghammerDepartment of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland; Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland.
Reza MaroofianDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom.
Rueda BadarDepartment of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland; Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland.
Anne GregorDepartment of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland; Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland.
Michelle RochmanDepartment of Neurology, Thomas Jefferson University, Philadelphia, PA.
Jeffrey B RatliffDepartment of Neurology, Thomas Jefferson University, Philadelphia, PA.
Marije KoopmansDepartment of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Theresia HergetInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Maja HempelInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Fanny KortümInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Delphine HeronDepartment of Genetics, La Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.
Cyril MignotDepartment of Genetics, La Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.
Boris KerenDepartment of Genetics, La Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.
Susan BrooksDivision of Medical Genetics, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
Christina BottiDivision of Medical Genetics, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
Bruria Ben-ZeevThe Neurology Department at Sheba Medical Center, Ramat Gan, Israel.
Emanuela ArgilliBrain Development Research Program, Department of Neurology, University of California San Francisco, San Francisco, CA.
Elliot H SherrBrain Development Research Program, Department of Neurology, University of California San Francisco, San Francisco, CA.
Vykuntaraju K GowdaDepartment of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India.
Varunvenkat M SrinivasanDepartment of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India.
Somayeh BakhtiariPediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ; Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ.
Michael C KruerPediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ; Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ.
Mustafa A SalihDivision of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Pediatrics, College of Medicine, Almughtaribeen University, Khartoum, Sudan.
Alma KuechlerInstitute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Eric A MullerClinical Genetics, Stanford Children's Health, San Francisco, CA.
Karli BlockerClinical Genetics, Stanford Children's Health, San Francisco, CA.
Outi KuisminDepartment of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
Kristen L ParkAnschutz Medical Campus Department of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO.
Aaina KochharSection of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
Kathleen BrownSection of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
Subhadra RamanathanDivision of Genetics, Loma Linda University Health, San Bernardino, CA.
Robin D ClarkDivision of Genetics, Loma Linda University Health, San Bernardino, CA.
Magdeldin ElgizouliInstitute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Gia MelikishviliDepartment of pediatrics, MediClubGeorgia Medical Center, Tbilisi, Georgia.
Nazhi TabatadzeDepartment of pediatrics, MediClubGeorgia Medical Center, Tbilisi, Georgia.
Zornitza StarkVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
Ghayda M MirzaaCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA; Department of Pediatrics, University of Washington, Seattle, WA; Brotman Baty Institute for Precision Medicine, Seattle, WA.
Jinfon OngChild Neurology Consultants of Austin, Austin, TX.
Ute GrasshoffInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Andrea BevotDepartment of Pediatric Neurology and Developmental Medicine, Children's Hospital, University Hospital of Tuebingen, Tuebingen, Germany.
Lydia von WintzingerodeInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Rami A JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Yvonne HennigDepartment of Pediatrics, University of Leipzig Medical Center, Leipzig, Germany.
Paula GoldenbergDivision of Medical Genetics, Massachusetts General Hospital, Boston, MA.
Chadi Al AlamPediatric Neurology Department, American Center for Psychiatry and Neurology, Abu Dhabi, United Arab Emirates; Pediatric Neurology department, Haykel Hospital, El Koura, Lebanon.
Majida CharifGenetics Unit, Medical Sciences Research Laboratory, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco; BRO Biobank, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco; Genetics and Immuno-Cell Therapy Team, Mohammed First University, Oujda, Morocco.
Redouane BoulouizGenetics Unit, Medical Sciences Research Laboratory, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco; BRO Biobank, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco.
Mohammed BellaouiGenetics Unit, Medical Sciences Research Laboratory, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco; BRO Biobank, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco.
Rim AmraniDepartment of Neonatology, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco.
Fuad Al MutairiGenetic and Precision Medicine Department, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
Abdullah M TamimPediatric Neurology Section-Pediatric Department, King Faisal Specialist Hospital & Research Center (Gen. Org) - Jeddah Branch, Riyadh, Saudi Arabia.
Firdous AbdulwahabDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Ebtissal M KhoujDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Javeria R AlviDepartment of Pediatric Neurology, Children's Hospital and Institute of Child Health, Lahore, Pakistan.
Tipu SultanDepartment of Pediatric Neurology, Children's Hospital and Institute of Child Health, Lahore, Pakistan.
Narges HashemiDepartment of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Ehsan G KarimianiMolecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London, United Kingdom.
Farah AshrafzadehDepartment of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Shima ImannezhadDepartment of Pediatric Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Stephanie EfthymiouDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom.
Henry HouldenDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom.
Heinrich StichtInstitute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Christiane ZweierDepartment of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland; Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland. Electronic address: christiane.zweier@insel.ch.
King Faisal Specialist Hospital & Research Centre · SAMohamed I University · MAUniversity of Bern · CHLeipzig University · DEMashhad University of Medical Sciences · IRNational Hospital for Neurology and Neurosurgery · GBSorbonne Université · FRUniversität Hamburg · DEBarrow Neurological Institute · USIndira Gandhi Institute of Child Health · INLoma Linda University · USRutgers, The State University of New Jersey · USStanford Health Care · USThomas Jefferson University · USUniversity of California, San Francisco · USUniversity of Colorado Denver · USUniversity of Duisburg-Essen · DEAbu Dhabi Falcon Hospital · AEFriedrich-Alexander-Universität Erlangen-Nürnberg · DEKing Saud bin Abdulaziz University for Health Sciences · SA
Funding
De novo copy number variation and gene discovery in human brain malformationsR01NS058721 · NINDS · UNIVERSITY OF CHICAGO · PI ARGILLI, EMANUELA · 2008 to 2025
$10.9MGenomic Insights into the Neurobiology of Cerebral PalsyR01NS106298 · NINDS · UNIVERSITY OF ARIZONA · PI KRUER, MICHAEL C · 2019 to 2023
$3.7MNINDS NIH HHS R01 NS058721
Abstract
purposeMissense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability.
methodsBy international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro.
resultsIn accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well.
conclusionBy identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders.
Indexed as
EpilepsyIntellectual DisabilityNeurodevelopmental DisordersGenetic Association StudiesGTP-Binding ProteinsGTP PhosphohydrolasesHumansPhenotypeTumor Suppressor ProteinsGTP-Binding ProteinsGTP PhosphohydrolasesRHOBTB2 protein, humanTumor Suppressor ProteinsDevelopmental and epileptic encephalopathyIntellectual disabilityNeurodevelopmental disorderRHOBTB2Seizures
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