ArticleAmerican journal of human genetics2022
Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.
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Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 16 papers.
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16citing papers in PubMed
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Who cites it
16 citing papers in PubMed.
- From chromatin dynamics to brain disease: Polycomb-Trithorax mechanisms in neurodevelopment.Trends in neurosciences · 2026Review
- Allosteric network of dynamic coupling within BAP1-UCH revealed by methyl NMR.Nature communications · 2026Article
- Phenotype-Specific Recalibration of MAVE Data Enables Repurposing ofmedRxiv : the preprint server for health sciences · 2026Article
- Knockdown of PR-DUB subunit calypso in the developing Drosophila eye and wing results in mis-patterned tissues with altered size and shape.G3 (Bethesda, Md.) · 2025Article
- Polycomb repressive complexes 1 and 2 independently and dynamically regulate euchromatin during cerebellar neurodevelopment.PLoS genetics · 2025Article
- An overview of BAP1 biological functions and current therapeutics.Biochimica et biophysica acta. Reviews on cancer · 2025Review
- Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR-ncPRC1.1.Genes & development · 2025Article
- Pathogenic Germline Variants in Uveal Melanoma Driver and BAP1-Associated Genes in Finnish Patients with Uveal Melanoma.Pigment cell & melanoma research · 2025Article
- O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG): Potential mechanistic targets revealed by evaluating the OGT interactome.The Journal of biological chemistry · 2024Review
- Saturation genome editing of BAP1 functionally classifies somatic and germline variants.Nature genetics · 2024Article
- Germline findings in cancer predisposing genes from a small cohort of chordoma patients.Journal of cancer research and clinical oncology · 2024Article
- H2A monoubiquitination: insights from human genetics and animal models.Human genetics · 2024Review
- BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system.The Journal of clinical investigation · 2024Article
- Functional assay for assessment of pathogenicity of BAP1 variants.Human molecular genetics · 2024Article
- Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases.American journal of human genetics · 2024Article
- Heritability and genetic contribution analysis of structural-functional coupling in human brain.Imaging neuroscience (Cambridge, Mass.) · 2024Article
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Authors and funding
59 authors.
Sébastien KüryService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France. Electronic address: sebastien.kury@chu-nantes.fr.
Frédéric EbsteinInstitut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.
Alice MolléUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, 44000 Nantes, France.
Thomas BesnardService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
Ming-Kang LeeInstitut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France; INSERM U934/CNRS UMR 3215, 75248 Paris, France.
Virginie VignardService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
Tiphaine HeryInstitut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France; INSERM U934/CNRS UMR 3215, 75248 Paris, France.
Mathilde NizonService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
Grazia M S ManciniDepartment of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, 3015 Rotterdam, the Netherlands.
Jacques C GiltayDivision Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 Utrecht, the Netherlands.
Benjamin CognéService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
Kirsty McWalterGeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Wallid DebService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
Hagar Mor-ShakedDepartment of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem 9112001, Israel.
Hong LiDepartment of Human Genetics and Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Rhonda E SchnurGeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Ingrid M WentzensenGeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Anne-Sophie Denommé-PichonCHU Angers, Département de Biochimie et Génétique, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083, Université d'Angers, 49933 Angers Cedex 9, France.
Cynthia FourgeuxUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, 44000 Nantes, France.
Frans W VerheijenDepartment of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, 3015 Rotterdam, the Netherlands.
Eva FaurieService de Génétique Médicale, CHU Nantes, 44093 Nantes, France.
Rachel SchotDepartment of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, 3015 Rotterdam, the Netherlands.
Cathy A StevensDepartment of Pediatrics, University of Tennessee College of Medicine, Chattanooga, TN 37403, USA.
Daphne J SmitsDepartment of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, 3015 Rotterdam, the Netherlands.
Eileen BarrDepartment of Human Genetics and Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Ruth ShefferDepartment of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem 9112001, Israel.
Jonathan A BernsteinDepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA 94304, USA.
Chandler L StimachDepartment of Human Genetics and Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Eliana KovitchPANDA, 5887 Glenridge Drive, Suite 140, Atlanta, GA 30328, USA.
Vandana ShashiDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Kelly SchochDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Whitney SmithPANDA, 5887 Glenridge Drive, Suite 140, Atlanta, GA 30328, USA.
Richard H van JaarsveldDivision Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 Utrecht, the Netherlands.
Anna C E HurstDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Kirstin SmithDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Evan H BaughGenomic Medicine, Columbia University, New York, NY 10032, USA.
Suzanne G BohmDivision Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 Utrecht, the Netherlands.
Emílie VyhnálkováDepartment of Biology and Medical Genetics, 2nd School of Medicine, Charles University in Prague and Faculty Hospital Motol, V Úvalu 84, 150 06 Prague 5, Czech Republic.
Lukáš RybaDepartment of Biology and Medical Genetics, 2nd School of Medicine, Charles University in Prague and Faculty Hospital Motol, V Úvalu 84, 150 06 Prague 5, Czech Republic.
Capucine DelnatteService de Génétique Médicale, CHU Nantes, 44093 Nantes, France.
Juanita NeiraDepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Dominique BonneauCHU Angers, Département de Biochimie et Génétique, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083, Université d'Angers, 49933 Angers Cedex 9, France.
Annick ToutainService de Génétique, Centre Hospitalier Régional Universitaire, 37044 Tours, France; UMR 1253, iBrain, Université de Tours, INSERM, 37032 Tours, France.
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratory, Houston, TX 77021, USA.
Undiagnosed Diseases Network
Séverine Audebert-BellangerCHRU Brest, Génétique Médicale, 29609 Brest, France.
Brigitte Gilbert-DussardierCHU Poitiers, Service de Génétique, BP577, 86021 Poitiers, France; EA 3808, Université Poitiers, 86034 Poitiers, France.
Sylvie OdentService de Génétique Clinique, Centre Référence "Déficiences Intellectuelles de causes rares," Centre de Référence Anomalies du Développement CLAD-Ouest, ERN ITHACA, CHU Rennes, 35203 Rennes, France; CNRS UMR 6290 IGDR "Institut de Génétique et développement de Rennes," Université de Rennes, 2 Avenue du Professeur Léon Bernard, 35043 Rennes, France.
Frédéric LaumonnierService de Génétique, Centre Hospitalier Régional Universitaire, 37044 Tours, France; UMR 1253, iBrain, Université de Tours, INSERM, 37032 Tours, France.
Seth I BergerCenter for Genetic Medicine Research/Rare Disease Institute, Children's National Medical Center, Washington, DC 20010, USA.
Ann C M SmithOffice of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, 10/10C103, MSC 1851, Bethesda, MD 20892, USA.
Franck BourdeautInstitut Curie, SIREDO (Care, Innovation, Research in Pediatric, Adolescent and Young Adults Oncology), 75005 Paris, France.
Marc-Henri SternInstitut Curie, PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma, Equipe Labellisée Par la Ligue Nationale Contre le Cancer, 75248 Paris, France.
Richard RedonUniversité de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
Elke KrügerInstitut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.
Raphaël MargueronInstitut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France; INSERM U934/CNRS UMR 3215, 75248 Paris, France.
Stéphane BézieauService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
Jeremie PoschmannUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, 44000 Nantes, France.
Bertrand IsidorService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France. Electronic address: bertrand.isidor@chu-nantes.fr.
Funding
An integrated and diverse genomic medicine program for undiagnosed diseasesU01HG007672 · NHGRI · DUKE UNIVERSITY · PI SHASHI, VANDANA · 2014 to 2022
$13.4MNHGRI NIH HHS U01 HG007672
Abstract
Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.
Indexed as
Germ-Line MutationLoss of Function MutationMutation, MissenseAdolescentBRCA1 ProteinChildChild, PreschoolChromatinChromatin Assembly and DisassemblyFamilyFemaleGene Expression RegulationHeterozygoteHistonesHost Cell Factor C1HumansBAP1 protein, humanBARD1 protein, humanBRCA1 ProteinBRCA1 protein, humanChromatinHCFC1 protein, humanHistonesHost Cell Factor C1Proteasome Endopeptidase ComplexTumor Suppressor ProteinsUbiquitinUbiquitin-Protein LigasesUbiquitin ThiolesteraseBAP1BRCA1cancerchromatin remodelingdeubiquitinationhistone 2Aintellectual disabilityneurodevelopmenttumorubiquitinubiquitin-proteasome systemUPS
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NCT02450851ClinicalTrials.gov
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