Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals

Quentin Sabbagh; Sadegheh Haghshenas; Juliette Piard; Chloé Trouvé; Jeanne Amiel; Tania Attié-Bitach; Tugce Balci; Mouna Barat-Houari; Alyce Belonis; Odile Boute; Diana S. Brightman; Ange-Line Bruel; Stefano Giuseppe Caraffi; Nicolas Chatron; Corinne Collet; William Dufour; Patrick Edery; Chin-To Fong; Carlo Fusco; Vincent Gatinois; Evan Gouy; Anne-Marie Guerrot; Solveig Heide; Aakash Joshi; Natalya Karp; Boris Keren; Marion Lesieur-Sebellin; Jonathan Levy; Michael A. Levy; Claire Lozano; Stanislas Lyonnet; Henri Margot; Pauline Marzin; Haley McConkey; Vincent Michaud; Gaël Nicolas; Mevyn Nizard; Alix Paulet; Francesca Peluso; Vincent Pernin; Laurence Perrin; Christophe Philippe; Chitra Prasad; Madhavi Prasad; Raissa Relator; Marlène Rio; Sophie Rondeau; Valentin Ruault; Nathalie Ruiz-Pallares; Elodie Sanchez; Debbie Shears; Victoria Mok Siu; Arthur Sorlin; Matthew Tedder; Mylène Tharreau; Frédéric Tran Mau-Them; Liselot van der Laan; Julien van Gils; Alain Verloes; Sandra Whalen; Marjolaine Willems; K. vin Yauy; Roberta Zuntini; Jennifer Kerkhof; Bekim Sadikovic; David Geneviève

doi:10.1016/j.gim.2023.101007

Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals

Quentin Sabbagh, Sadegheh Haghshenas, Juliette Piard, Chloé Trouvé, Jeanne Amiel, Tania Attié-Bitach, Tugce Balci, Mouna Barat-Houari, Alyce Belonis, Odile Boute, Diana S. Brightman, Ange-Line Bruel, Stefano Giuseppe Caraffi, Nicolas Chatron, Corinne Collet, William Dufour, Patrick Edery, Chin-To Fong, Carlo Fusco, Vincent GatinoisEvan Gouy, Anne-Marie Guerrot, Solveig Heide, Aakash Joshi, Natalya Karp, Boris Keren, Marion Lesieur-Sebellin, Jonathan Levy, Michael A. Levy, Claire Lozano, Stanislas Lyonnet, Henri Margot, Pauline Marzin, Haley McConkey, Vincent Michaud, Gaël Nicolas, Mevyn Nizard, Alix Paulet, Francesca Peluso, Vincent Pernin, Laurence Perrin, Christophe Philippe, Chitra Prasad, Madhavi Prasad, Raissa Relator, Marlène Rio, Sophie Rondeau, Valentin Ruault, Nathalie Ruiz-Pallares, Elodie Sanchez, Debbie Shears, Victoria Mok Siu, Arthur Sorlin, Matthew Tedder, Mylène Tharreau, Frédéric Tran Mau-Them, Liselot van der Laan, Julien van Gils, Alain Verloes, Sandra Whalen, Marjolaine Willems, K. vin Yauy, Roberta Zuntini, Jennifer Kerkhof, Bekim Sadikovic, David Geneviève

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

Abstract

Purpose: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition. Methods: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature. Results: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4+ T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8+ T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled. Conclusion: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene.

Original language	English
Article number	101007
Journal	Genetics in medicine
Volume	26
Issue number	1
DOIs	https://doi.org/10.1016/j.gim.2023.101007
Publication status	Published - 1 Jan 2024

Keywords

BCL11B
Epigenetic signature
Neurodevelopmental delay
T cells

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10.1016/j.gim.2023.101007

Cite this

Sabbagh, Q., Haghshenas, S., Piard, J., Trouvé, C., Amiel, J., Attié-Bitach, T., Balci, T., Barat-Houari, M., Belonis, A., Boute, O., Brightman, D. S., Bruel, A.-L., Caraffi, S. G., Chatron, N., Collet, C., Dufour, W., Edery, P., Fong, C.-T., Fusco, C., ... Geneviève, D. (2024). Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals. Genetics in medicine, 26(1), Article 101007. https://doi.org/10.1016/j.gim.2023.101007

@article{667f92f70b5c45d9b8ed32dc11aa8ab5,

title = "Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals",

abstract = "Purpose: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition. Methods: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature. Results: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4+ T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8+ T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled. Conclusion: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene.",

keywords = "BCL11B, Epigenetic signature, Neurodevelopmental delay, T cells",

author = "Quentin Sabbagh and Sadegheh Haghshenas and Juliette Piard and Chlo{\'e} Trouv{\'e} and Jeanne Amiel and Tania Atti{\'e}-Bitach and Tugce Balci and Mouna Barat-Houari and Alyce Belonis and Odile Boute and Brightman, {Diana S.} and Ange-Line Bruel and Caraffi, {Stefano Giuseppe} and Nicolas Chatron and Corinne Collet and William Dufour and Patrick Edery and Chin-To Fong and Carlo Fusco and Vincent Gatinois and Evan Gouy and Anne-Marie Guerrot and Solveig Heide and Aakash Joshi and Natalya Karp and Boris Keren and Marion Lesieur-Sebellin and Jonathan Levy and Levy, {Michael A.} and Claire Lozano and Stanislas Lyonnet and Henri Margot and Pauline Marzin and Haley McConkey and Vincent Michaud and Ga{\"e}l Nicolas and Mevyn Nizard and Alix Paulet and Francesca Peluso and Vincent Pernin and Laurence Perrin and Christophe Philippe and Chitra Prasad and Madhavi Prasad and Raissa Relator and Marl{\`e}ne Rio and Sophie Rondeau and Valentin Ruault and Nathalie Ruiz-Pallares and Elodie Sanchez and Debbie Shears and Siu, {Victoria Mok} and Arthur Sorlin and Matthew Tedder and Myl{\`e}ne Tharreau and Mau-Them, {Fr{\'e}d{\'e}ric Tran} and {van der Laan}, Liselot and {van Gils}, Julien and Alain Verloes and Sandra Whalen and Marjolaine Willems and Yauy, {K. vin} and Roberta Zuntini and Jennifer Kerkhof and Bekim Sadikovic and David Genevi{\`e}ve",

note = "Publisher Copyright: {\textcopyright} 2023 American College of Medical Genetics and Genomics",

year = "2024",

month = jan,

day = "1",

doi = "10.1016/j.gim.2023.101007",

language = "English",

volume = "26",

journal = "Genetics in medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "1",

}

Sabbagh, Q, Haghshenas, S, Piard, J, Trouvé, C, Amiel, J, Attié-Bitach, T, Balci, T, Barat-Houari, M, Belonis, A, Boute, O, Brightman, DS, Bruel, A-L, Caraffi, SG, Chatron, N, Collet, C, Dufour, W, Edery, P, Fong, C-T, Fusco, C, Gatinois, V, Gouy, E, Guerrot, A-M, Heide, S, Joshi, A, Karp, N, Keren, B, Lesieur-Sebellin, M, Levy, J, Levy, MA, Lozano, C, Lyonnet, S, Margot, H, Marzin, P, McConkey, H, Michaud, V, Nicolas, G, Nizard, M, Paulet, A, Peluso, F, Pernin, V, Perrin, L, Philippe, C, Prasad, C, Prasad, M, Relator, R, Rio, M, Rondeau, S, Ruault, V, Ruiz-Pallares, N, Sanchez, E, Shears, D, Siu, VM, Sorlin, A, Tedder, M, Tharreau, M, Mau-Them, FT, van der Laan, L, van Gils, J, Verloes, A, Whalen, S, Willems, M, Yauy, KV, Zuntini, R, Kerkhof, J, Sadikovic, B & Geneviève, D 2024, 'Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals', Genetics in medicine, vol. 26, no. 1, 101007. https://doi.org/10.1016/j.gim.2023.101007

TY - JOUR

T1 - Clinico-biological refinement of BCL11B-related disorder and identification of an episignature

T2 - A series of 20 unreported individuals

AU - Sabbagh, Quentin

AU - Haghshenas, Sadegheh

AU - Piard, Juliette

AU - Trouvé, Chloé

AU - Amiel, Jeanne

AU - Attié-Bitach, Tania

AU - Balci, Tugce

AU - Barat-Houari, Mouna

AU - Belonis, Alyce

AU - Boute, Odile

AU - Brightman, Diana S.

AU - Bruel, Ange-Line

AU - Caraffi, Stefano Giuseppe

AU - Chatron, Nicolas

AU - Collet, Corinne

AU - Dufour, William

AU - Edery, Patrick

AU - Fong, Chin-To

AU - Fusco, Carlo

AU - Gatinois, Vincent

AU - Gouy, Evan

AU - Guerrot, Anne-Marie

AU - Heide, Solveig

AU - Joshi, Aakash

AU - Karp, Natalya

AU - Keren, Boris

AU - Lesieur-Sebellin, Marion

AU - Levy, Jonathan

AU - Levy, Michael A.

AU - Lozano, Claire

AU - Lyonnet, Stanislas

AU - Margot, Henri

AU - Marzin, Pauline

AU - McConkey, Haley

AU - Michaud, Vincent

AU - Nicolas, Gaël

AU - Nizard, Mevyn

AU - Paulet, Alix

AU - Peluso, Francesca

AU - Pernin, Vincent

AU - Perrin, Laurence

AU - Philippe, Christophe

AU - Prasad, Chitra

AU - Prasad, Madhavi

AU - Relator, Raissa

AU - Rio, Marlène

AU - Rondeau, Sophie

AU - Ruault, Valentin

AU - Ruiz-Pallares, Nathalie

AU - Sanchez, Elodie

AU - Shears, Debbie

AU - Siu, Victoria Mok

AU - Sorlin, Arthur

AU - Tedder, Matthew

AU - Tharreau, Mylène

AU - Mau-Them, Frédéric Tran

AU - van der Laan, Liselot

AU - van Gils, Julien

AU - Verloes, Alain

AU - Whalen, Sandra

AU - Willems, Marjolaine

AU - Yauy, K. vin

AU - Zuntini, Roberta

AU - Kerkhof, Jennifer

AU - Sadikovic, Bekim

AU - Geneviève, David

PY - 2024/1/1

Y1 - 2024/1/1

N2 - Purpose: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition. Methods: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature. Results: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4+ T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8+ T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled. Conclusion: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene.

AB - Purpose: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition. Methods: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature. Results: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4+ T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8+ T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled. Conclusion: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene.

KW - BCL11B

KW - Epigenetic signature

KW - Neurodevelopmental delay

KW - T cells

UR - http://www.scopus.com/inward/record.url?scp=85178351986&partnerID=8YFLogxK

U2 - 10.1016/j.gim.2023.101007

DO - 10.1016/j.gim.2023.101007

M3 - Article

C2 - 37860968

SN - 1098-3600

VL - 26

JO - Genetics in medicine

JF - Genetics in medicine

IS - 1

M1 - 101007

ER -

Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals

Abstract

Keywords

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