2. Academic Validation
  3. Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

  • Am J Hum Genet. 2022 Feb 3;109(2):361-372. doi: 10.1016/j.ajhg.2021.12.011.
Sébastien Küry 1,  Frédéric Ebstein 2,  Alice Mollé 3,  Thomas Besnard 4,  Ming-Kang Lee 5,  Virginie Vignard 4,  Tiphaine Hery 5,  Mathilde Nizon 4,  Grazia M S Mancini 6,  Jacques C Giltay 7,  Benjamin Cogné 4,  Kirsty McWalter 8,  Wallid Deb 4,  Hagar Mor-Shaked 9,  Hong Li 10,  Rhonda E Schnur 8,  Ingrid M Wentzensen 8,  Anne-Sophie Denommé-Pichon 11,  Cynthia Fourgeux 3,  Frans W Verheijen 6,  Eva Faurie 12,  Rachel Schot 6,  Cathy A Stevens 13,  Daphne J Smits 6,  Eileen Barr 10,  Ruth Sheffer 9,  Jonathan A Bernstein 14,  Chandler L Stimach 10,  Eliana Kovitch 15,  Vandana Shashi 16,  Kelly Schoch 16,  Whitney Smith 15,  Richard H van Jaarsveld 7,  Anna C E Hurst 17,  Kirstin Smith 17,  Evan H Baugh 18,  Suzanne G Bohm 7,  Emílie Vyhnálková 19,  Lukáš Ryba 19,  Capucine Delnatte 12,  Juanita Neira 20,  Dominique Bonneau 11,  Annick Toutain 21,  Jill A Rosenfeld 22,  Undiagnosed Diseases Network,  Séverine Audebert-Bellanger 23,  Brigitte Gilbert-Dussardier 24,  Sylvie Odent 25,  Frédéric Laumonnier 21,  Seth I Berger 26,  Ann C M Smith 27,  Franck Bourdeaut 28,  Marc-Henri Stern 29,  Richard Redon 30,  Elke Krüger 2,  Raphaël Margueron 5,  Stéphane Bézieau 4,  Jeremie Poschmann 3,  Bertrand Isidor 31
Affiliations

Affiliations

  • 1 Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France. Electronic address: [email protected].
  • 2 Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.
  • 3 Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, 44000 Nantes, France.
  • 4 Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
  • 5 Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France; INSERM U934/CNRS UMR 3215, 75248 Paris, France.
  • 6 Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, 3015 Rotterdam, the Netherlands.
  • 7 Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 Utrecht, the Netherlands.
  • 8 GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 9 Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem 9112001, Israel.
  • 10 Department of Human Genetics and Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
  • 11 CHU Angers, Département de Biochimie et Génétique, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083, Université d'Angers, 49933 Angers Cedex 9, France.
  • 12 Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France.
  • 13 Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, TN 37403, USA.
  • 14 Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94304, USA.
  • 15 PANDA, 5887 Glenridge Drive, Suite 140, Atlanta, GA 30328, USA.
  • 16 Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
  • 17 Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  • 18 Genomic Medicine, Columbia University, New York, NY 10032, USA.
  • 19 Department 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.
  • 20 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 21 Service de Génétique, Centre Hospitalier Régional Universitaire, 37044 Tours, France; UMR 1253, iBrain, Université de Tours, INSERM, 37032 Tours, France.
  • 22 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratory, Houston, TX 77021, USA.
  • 23 CHRU Brest, Génétique Médicale, 29609 Brest, France.
  • 24 CHU Poitiers, Service de Génétique, BP577, 86021 Poitiers, France; EA 3808, Université Poitiers, 86034 Poitiers, France.
  • 25 Service 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.
  • 26 Center for Genetic Medicine Research/Rare Disease Institute, Children's National Medical Center, Washington, DC 20010, USA.
  • 27 Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, 10/10C103, MSC 1851, Bethesda, MD 20892, USA.
  • 28 Institut Curie, SIREDO (Care, Innovation, Research in Pediatric, Adolescent and Young Adults Oncology), 75005 Paris, France.
  • 29 Institut Curie, PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma, Equipe Labellisée Par la Ligue Nationale Contre le Cancer, 75248 Paris, France.
  • 30 Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
  • 31 Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France. Electronic address: [email protected].
PMID: 35051358 DOI: 10.1016/j.ajhg.2021.12.011
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.

Keywords

BAP1; BRCA1; UPS; cancer; chromatin remodeling; deubiquitination; histone 2A; intellectual disability; neurodevelopment; tumor; ubiquitin; ubiquitin-proteasome system.

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