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

Sébastien Küry 1, 2, * Frédéric Ebstein 3 Alice Mollé 4 Thomas Besnard 1, 2 Ming-Kang Lee 5 Virginie Vignard 2 Tiphaine Hery 5 Mathilde Nizon 2 Grazia M.S. Mancini 6 Jacques Giltay 7 Benjamin Cogné 2 Kirsty Mcwalter 8 Wallid Deb 2 Hagar Mor-Shaked 9 Hong Li 10 Rhonda Schnur 8 Ingrid Wentzensen 8 Anne-Sophie Denommé-Pichon 11, 12 Cynthia Fourgeux 4 Frans Verheijen Eva Faurie 1 Rachel Schot Cathy Stevens 13 Daphne Smits Eileen Barr Ruth Sheffer Jonathan Bernstein 14 Chandler Stimach Eliana Kovitch Vandana Shashi 15 Kelly Schoch Whitney Smith Richard van Jaarsveld Anna C.E. Hurst 16 Kirstin Smith Evan Baugh 17 Suzanne Bohm Emílie Vyhnálková 18 Lukáš Ryba Capucine Delnatte Juanita Neira Dominique Bonneau 19, 12 Annick Toutain 20 Jill Rosenfeld 21 Séverine Audebert-Bellanger 22 Brigitte Gilbert-Dussardier 23 Sylvie Odent 24, 25, 26 Frédéric Laumonnier 20 Seth Berger 27 Ann C.M. Smith 28 Franck Bourdeaut 29 Marc-Henri Stern 30 Richard Redon 2, 1 Elke Krüger 31 Raphaël Margueron 5 Stéphane Bézieau 2, 1 Jeremie Poschmann 4 Bertrand Isidor 2, 1, * 
* Corresponding author
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.
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Submitted on : Tuesday, July 19, 2022 - 9:58:08 AM
Last modification on : Sunday, September 4, 2022 - 6:15:39 PM



Sébastien Küry, Frédéric Ebstein, Alice Mollé, Thomas Besnard, Ming-Kang Lee, et al.. Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder. American Journal of Human Genetics, Elsevier (Cell Press), 2022, 109 (2), pp.361-372. ⟨10.1016/j.ajhg.2021.12.011⟩. ⟨hal-03661178⟩



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