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 Fourgeux; Frans 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

doi:10.1016/j.ajhg.2021.12.011

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

Clinical Genetics

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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 language	English
Pages (from-to)	361-372
Number of pages	12
Journal	American Journal of Human Genetics
Volume	109
Issue number	2
Early online date	3 Feb 2022
DOIs	https://doi.org/10.1016/j.ajhg.2021.12.011
Publication status	Published - 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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Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorderFinal published version, 1.88 MBLicence: CC BY-NC-ND

Cite this

Küry, S., Ebstein, F., Undiagnosed Diseases Network, Mollé, A., Besnard, T., Lee, M. K., Vignard, V., Hery, T., Nizon, M., Mancini, G. M. S., Giltay, J. C., Cogné, B., McWalter, K., Deb, W., Mor-Shaked, H., Li, H., Schnur, R. E., Wentzensen, I. M., Denommé-Pichon, A. S., ... Smith, A. C. M. (2022). Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder. American Journal of Human Genetics, 109(2), 361-372. https://doi.org/10.1016/j.ajhg.2021.12.011

@article{04660f4b5cf74e0592ca6cc161e07f2b,

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

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.",

author = "S{\'e}bastien K{\"u}ry and Fr{\'e}d{\'e}ric Ebstein and {Undiagnosed Diseases Network} and Alice Moll{\'e} and Thomas Besnard and Lee, {Ming Kang} and Virginie Vignard and Tiphaine Hery and Mathilde Nizon and Mancini, {Grazia M.S.} and Giltay, {Jacques C.} and Benjamin Cogn{\'e} and Kirsty McWalter and Wallid Deb and Hagar Mor-Shaked and Hong Li and Schnur, {Rhonda E.} and Wentzensen, {Ingrid M.} and Denomm{\'e}-Pichon, {Anne Sophie} and Cynthia Fourgeux and Verheijen, {Frans W.} and Eva Faurie and Rachel Schot and Stevens, {Cathy A.} and Smits, {Daphne J.} and Eileen Barr and Ruth Sheffer and Bernstein, {Jonathan A.} and Stimach, {Chandler L.} and Eliana Kovitch and Vandana Shashi and Kelly Schoch and Whitney Smith and {van Jaarsveld}, {Richard H.} and Hurst, {Anna C.E.} and Kirstin Smith and Baugh, {Evan H.} and Bohm, {Suzanne G.} and Em{\'i}lie Vyhn{\'a}lkov{\'a} and Luk{\'a}{\v s} Ryba and Capucine Delnatte and Juanita Neira and Dominique Bonneau and Annick Toutain and Rosenfeld, {Jill A.} and S{\'e}verine Audebert-Bellanger and Brigitte Gilbert-Dussardier and Sylvie Odent and Fr{\'e}d{\'e}ric Laumonnier and Berger, {Seth I.} and Smith, {Ann C.M.}",

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 Fr{\'e}d{\'e}rique Allaire from the Health Regional Agency of Poitou-Charentes for supporting this project. We thank L{\'e}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. Publisher Copyright: {\textcopyright} 2021 American Society of Human Genetics",

year = "2022",

month = feb,

day = "3",

doi = "10.1016/j.ajhg.2021.12.011",

language = "English",

volume = "109",

pages = "361--372",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

Küry, S, Ebstein, F, Undiagnosed Diseases Network, Mollé, A, Besnard, T, Lee, MK, Vignard, V, Hery, T, Nizon, M, Mancini, GMS, Giltay, JC, Cogné, B, McWalter, K, Deb, W, Mor-Shaked, H, Li, H, Schnur, RE, Wentzensen, IM, Denommé-Pichon, AS, Fourgeux, C, Verheijen, FW, Faurie, E, Schot, R, Stevens, CA, Smits, DJ, Barr, E, Sheffer, R, Bernstein, JA, Stimach, CL, Kovitch, E, Shashi, V, Schoch, K, Smith, W, van Jaarsveld, RH, Hurst, ACE, Smith, K, Baugh, EH, Bohm, SG, Vyhnálková, E, Ryba, L, Delnatte, C, Neira, J, Bonneau, D, Toutain, A, Rosenfeld, JA, Audebert-Bellanger, S, Gilbert-Dussardier, B, Odent, S, Laumonnier, F, Berger, SI & Smith, ACM 2022, 'Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder', American Journal of Human Genetics, vol. 109, no. 2, pp. 361-372. https://doi.org/10.1016/j.ajhg.2021.12.011

TY - JOUR

T1 - Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

AU - Küry, Sébastien

AU - Ebstein, Frédéric

AU - Undiagnosed Diseases Network

AU - Mollé, Alice

AU - Besnard, Thomas

AU - Lee, Ming Kang

AU - Vignard, Virginie

AU - Hery, Tiphaine

AU - Nizon, Mathilde

AU - Mancini, Grazia M.S.

AU - Giltay, Jacques C.

AU - Cogné, Benjamin

AU - McWalter, Kirsty

AU - Deb, Wallid

AU - Mor-Shaked, Hagar

AU - Li, Hong

AU - Schnur, Rhonda E.

AU - Wentzensen, Ingrid M.

AU - Denommé-Pichon, Anne Sophie

AU - Fourgeux, Cynthia

AU - Verheijen, Frans W.

AU - Faurie, Eva

AU - Schot, Rachel

AU - Stevens, Cathy A.

AU - Smits, Daphne J.

AU - Barr, Eileen

AU - Sheffer, Ruth

AU - Bernstein, Jonathan A.

AU - Stimach, Chandler L.

AU - Kovitch, Eliana

AU - Shashi, Vandana

AU - Schoch, Kelly

AU - Smith, Whitney

AU - van Jaarsveld, Richard H.

AU - Hurst, Anna C.E.

AU - Smith, Kirstin

AU - Baugh, Evan H.

AU - Bohm, Suzanne G.

AU - Vyhnálková, Emílie

AU - Ryba, Lukáš

AU - Delnatte, Capucine

AU - Neira, Juanita

AU - Bonneau, Dominique

AU - Toutain, Annick

AU - Rosenfeld, Jill A.

AU - Audebert-Bellanger, Séverine

AU - Gilbert-Dussardier, Brigitte

AU - Odent, Sylvie

AU - Laumonnier, Frédéric

AU - Berger, Seth I.

AU - Smith, Ann C.M.

N1 - 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

PY - 2022/2/3

Y1 - 2022/2/3

N2 - 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.

AB - 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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U2 - 10.1016/j.ajhg.2021.12.011

DO - 10.1016/j.ajhg.2021.12.011

M3 - Article

C2 - 35051358

AN - SCOPUS:85123766414

SN - 0002-9297

VL - 109

SP - 361

EP - 372

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

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

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