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

Sébastien Küry*, Frédéric Ebstein, Undiagnosed Diseases Network, Alice Mollé, Thomas Besnard, Ming Kang Lee, Virginie Vignard, Tiphaine Hery, Mathilde Nizon, Grazia M.S. Mancini, Jacques C. Giltay, Benjamin Cogné, Kirsty McWalter, Wallid Deb, Hagar Mor-Shaked, Hong Li, Rhonda E. Schnur, Ingrid M. Wentzensen, Anne Sophie Denommé-Pichon, Cynthia FourgeuxFrans W. Verheijen, Eva Faurie, Rachel Schot, Cathy A. Stevens, Daphne J. Smits, Eileen Barr, Ruth Sheffer, Jonathan A. Bernstein, Chandler L. Stimach, Eliana Kovitch, Vandana Shashi, Kelly Schoch, Whitney Smith, Richard H. van Jaarsveld, Anna C.E. Hurst, Kirstin Smith, Evan H. Baugh, Suzanne G. Bohm, Emílie Vyhnálková, Lukáš Ryba, Capucine Delnatte, Juanita Neira, Dominique Bonneau, Annick Toutain, Jill A. Rosenfeld, Séverine Audebert-Bellanger, Brigitte Gilbert-Dussardier, Sylvie Odent, Frédéric Laumonnier, Seth I. Berger, Ann C.M. Smith

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)361-372
Number of pages12
JournalAmerican Journal of Human Genetics
Volume109
Issue number2
Early online date3 Feb 2022
DOIs
Publication statusPublished - 3 Feb 2022

Bibliographical note

Funding Information:
We would like to thank all the families for participating in this study. We acknowledge HUGODIMS (Western France exome-based trio approach project to identify genes involved in intellectual disability); funding for HUGODIMS (individual 5) is supported by a grant from the French Ministry of Health and from the Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107). We thank Fr?d?rique Allaire from the Health Regional Agency of Poitou-Charentes for supporting this project. We thank L?a Ferrand and Emilie Le Blanc for grant and data management. We are most grateful to the GenoBiRD core facility in Nantes (Biogenouest Genomics) for its technical support. Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672 to V.S. Further support was obtained by funding from the German Research Foundation (SFBTR 167 A4, GRK2719 B4) to E.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratory. K.Mc. R.E.S. and I.M.W. are employees of GeneDx, Inc.

Funding Information:
We would like to thank all the families for participating in this study. We acknowledge HUGODIMS (Western France exome-based trio approach project to identify genes involved in intellectual disability); funding for HUGODIMS (individual 5) is supported by a grant from the French Ministry of Health and from the Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107 ). We thank Frédérique Allaire from the Health Regional Agency of Poitou-Charentes for supporting this project. We thank Léa Ferrand and Emilie Le Blanc for grant and data management. We are most grateful to the GenoBiRD core facility in Nantes (Biogenouest Genomics) for its technical support. Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672 to V.S. Further support was obtained by funding from the German Research Foundation ( SFBTR 167 A4 , GRK2719 B4 ) to E.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2021 American Society of Human Genetics

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