Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder PMID: 35051358

Target-related Cytokines

2026-09-23

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

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].

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.