Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature

Richard H. van Jaarsveld; Jack Reilly; Marie Claire Cornips; Michael A. Hadders; Emanuele Agolini; Priyanka Ahimaz; Kwame Anyane-Yeboa; Severine Audebert Bellanger; Ellen van Binsbergen; Marie Jose van den Boogaard; Elise Brischoux-Boucher; Raymond C. Caylor; Andrea Ciolfi; Ton A.J. van Essen; Paolo Fontana; Saskia Hopman; Maria Iascone; Margaret M. Javier; Erik Jan Kamsteeg; Jennifer Kerkhof; Jun Kido; Hyung Goo Kim; Tjitske Kleefstra; Fortunato Lonardo; Abbe Lai; Dorit Lev; Michael A. Levy; M. E.Suzanne Lewis; Angie Lichty; Marcel M.A.M. Mannens; Naomichi Matsumoto; Idit Maya; Haley McConkey; Andre Megarbane; Vincent Michaud; Evelina Miele; Marcello Niceta; Antonio Novelli; Roberta Onesimo; Rolph Pfundt; Bernt Popp; Eloise Prijoles; Raissa Relator; Sylvia Redon; Dmitrijs Rots; Karen Rouault; Ken Saida; Jolanda Schieving; Marco Tartaglia; Romano Tenconi; Kevin Uguen; Nienke Verbeek; Christopher A. Walsh; Keren Yosovich; Christopher J. Yuskaitis; Giuseppe Zampino; Bekim Sadikovic; Mariëlle Alders; Renske Oegema

doi:10.1016/j.gim.2022.09.006

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature

Richard H. van Jaarsveld, Jack Reilly, Marie Claire Cornips, Michael A. Hadders, Emanuele Agolini, Priyanka Ahimaz, Kwame Anyane-Yeboa, Severine Audebert Bellanger, Ellen van Binsbergen, Marie Jose van den Boogaard, Elise Brischoux-Boucher, Raymond C. Caylor, Andrea Ciolfi, Ton A.J. van Essen, Paolo Fontana, Saskia Hopman, Maria Iascone, Margaret M. Javier, Erik Jan Kamsteeg, Jennifer KerkhofJun Kido, Hyung Goo Kim, Tjitske Kleefstra, Fortunato Lonardo, Abbe Lai, Dorit Lev, Michael A. Levy, M. E.Suzanne Lewis, Angie Lichty, Marcel M.A.M. Mannens, Naomichi Matsumoto, Idit Maya, Haley McConkey, Andre Megarbane, Vincent Michaud, Evelina Miele, Marcello Niceta, Antonio Novelli, Roberta Onesimo, Rolph Pfundt, Bernt Popp, Eloise Prijoles, Raissa Relator, Sylvia Redon, Dmitrijs Rots, Karen Rouault, Ken Saida, Jolanda Schieving, Marco Tartaglia, Romano Tenconi, Kevin Uguen, Nienke Verbeek, Christopher A. Walsh, Keren Yosovich, Christopher J. Yuskaitis, Giuseppe Zampino, Bekim Sadikovic^*, Mariëlle Alders^*, Renske Oegema^*

^*Corresponding author for this work

QBRI - Neurological Disorders Research Center

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

16 Citations (Scopus)

Abstract

Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. Methods: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. Results: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. Conclusion: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.

Original language	English
Pages (from-to)	49-62
Number of pages	14
Journal	Genetics in Medicine
Volume	25
Issue number	1
DOIs	https://doi.org/10.1016/j.gim.2022.09.006
Publication status	Published - Jan 2023

Keywords

Human Genetics
Kdm2b
MDEMs
Methylation signatures
Neurodevelopmental disorders

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10.1016/j.gim.2022.09.006

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van Jaarsveld, R. H., Reilly, J., Cornips, M. C., Hadders, M. A., Agolini, E., Ahimaz, P., Anyane-Yeboa, K., Bellanger, S. A., van Binsbergen, E., van den Boogaard, M. J., Brischoux-Boucher, E., Caylor, R. C., Ciolfi, A., van Essen, T. A. J., Fontana, P., Hopman, S., Iascone, M., Javier, M. M., Kamsteeg, E. J., ... Oegema, R. (2023). Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature. Genetics in Medicine, 25(1), 49-62. https://doi.org/10.1016/j.gim.2022.09.006

@article{04282d534cc54796b4b6a6f49e354d72,

title = "Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature",

abstract = "Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. Methods: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. Results: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. Conclusion: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.",

keywords = "Human Genetics, Kdm2b, MDEMs, Methylation signatures, Neurodevelopmental disorders",

author = "{van Jaarsveld}, {Richard H.} and Jack Reilly and Cornips, {Marie Claire} and Hadders, {Michael A.} and Emanuele Agolini and Priyanka Ahimaz and Kwame Anyane-Yeboa and Bellanger, {Severine Audebert} and {van Binsbergen}, Ellen and {van den Boogaard}, {Marie Jose} and Elise Brischoux-Boucher and Caylor, {Raymond C.} and Andrea Ciolfi and {van Essen}, {Ton A.J.} and Paolo Fontana and Saskia Hopman and Maria Iascone and Javier, {Margaret M.} and Kamsteeg, {Erik Jan} and Jennifer Kerkhof and Jun Kido and Kim, {Hyung Goo} and Tjitske Kleefstra and Fortunato Lonardo and Abbe Lai and Dorit Lev and Levy, {Michael A.} and Lewis, {M. E.Suzanne} and Angie Lichty and Mannens, {Marcel M.A.M.} and Naomichi Matsumoto and Idit Maya and Haley McConkey and Andre Megarbane and Vincent Michaud and Evelina Miele and Marcello Niceta and Antonio Novelli and Roberta Onesimo and Rolph Pfundt and Bernt Popp and Eloise Prijoles and Raissa Relator and Sylvia Redon and Dmitrijs Rots and Karen Rouault and Ken Saida and Jolanda Schieving and Marco Tartaglia and Romano Tenconi and Kevin Uguen and Nienke Verbeek and Walsh, {Christopher A.} and Keren Yosovich and Yuskaitis, {Christopher J.} and Giuseppe Zampino and Bekim Sadikovic and Mari{\"e}lle Alders and Renske Oegema",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2023",

month = jan,

doi = "10.1016/j.gim.2022.09.006",

language = "English",

volume = "25",

pages = "49--62",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "1",

}

van Jaarsveld, RH, Reilly, J, Cornips, MC, Hadders, MA, Agolini, E, Ahimaz, P, Anyane-Yeboa, K, Bellanger, SA, van Binsbergen, E, van den Boogaard, MJ, Brischoux-Boucher, E, Caylor, RC, Ciolfi, A, van Essen, TAJ, Fontana, P, Hopman, S, Iascone, M, Javier, MM, Kamsteeg, EJ, Kerkhof, J, Kido, J, Kim, HG, Kleefstra, T, Lonardo, F, Lai, A, Lev, D, Levy, MA, Lewis, MES, Lichty, A, Mannens, MMAM, Matsumoto, N, Maya, I, McConkey, H, Megarbane, A, Michaud, V, Miele, E, Niceta, M, Novelli, A, Onesimo, R, Pfundt, R, Popp, B, Prijoles, E, Relator, R, Redon, S, Rots, D, Rouault, K, Saida, K, Schieving, J, Tartaglia, M, Tenconi, R, Uguen, K, Verbeek, N, Walsh, CA, Yosovich, K, Yuskaitis, CJ, Zampino, G, Sadikovic, B, Alders, M & Oegema, R 2023, 'Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature', Genetics in Medicine, vol. 25, no. 1, pp. 49-62. https://doi.org/10.1016/j.gim.2022.09.006

TY - JOUR

T1 - Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature

AU - van Jaarsveld, Richard H.

AU - Reilly, Jack

AU - Cornips, Marie Claire

AU - Hadders, Michael A.

AU - Agolini, Emanuele

AU - Ahimaz, Priyanka

AU - Anyane-Yeboa, Kwame

AU - Bellanger, Severine Audebert

AU - van Binsbergen, Ellen

AU - van den Boogaard, Marie Jose

AU - Brischoux-Boucher, Elise

AU - Caylor, Raymond C.

AU - Ciolfi, Andrea

AU - van Essen, Ton A.J.

AU - Fontana, Paolo

AU - Hopman, Saskia

AU - Iascone, Maria

AU - Javier, Margaret M.

AU - Kamsteeg, Erik Jan

AU - Kerkhof, Jennifer

AU - Kido, Jun

AU - Kim, Hyung Goo

AU - Kleefstra, Tjitske

AU - Lonardo, Fortunato

AU - Lai, Abbe

AU - Lev, Dorit

AU - Levy, Michael A.

AU - Lewis, M. E.Suzanne

AU - Lichty, Angie

AU - Mannens, Marcel M.A.M.

AU - Matsumoto, Naomichi

AU - Maya, Idit

AU - McConkey, Haley

AU - Megarbane, Andre

AU - Michaud, Vincent

AU - Miele, Evelina

AU - Niceta, Marcello

AU - Novelli, Antonio

AU - Onesimo, Roberta

AU - Pfundt, Rolph

AU - Popp, Bernt

AU - Prijoles, Eloise

AU - Relator, Raissa

AU - Redon, Sylvia

AU - Rots, Dmitrijs

AU - Rouault, Karen

AU - Saida, Ken

AU - Schieving, Jolanda

AU - Tartaglia, Marco

AU - Tenconi, Romano

AU - Uguen, Kevin

AU - Verbeek, Nienke

AU - Walsh, Christopher A.

AU - Yosovich, Keren

AU - Yuskaitis, Christopher J.

AU - Zampino, Giuseppe

AU - Sadikovic, Bekim

AU - Alders, Mariëlle

AU - Oegema, Renske

PY - 2023/1

Y1 - 2023/1

N2 - Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. Methods: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. Results: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. Conclusion: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.

AB - Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. Methods: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. Results: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. Conclusion: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.

KW - Human Genetics

KW - Kdm2b

KW - MDEMs

KW - Methylation signatures

KW - Neurodevelopmental disorders

UR - http://www.scopus.com/inward/record.url?scp=85141320488&partnerID=8YFLogxK

U2 - 10.1016/j.gim.2022.09.006

DO - 10.1016/j.gim.2022.09.006

M3 - Article

C2 - 36322151

AN - SCOPUS:85141320488

SN - 1098-3600

VL - 25

SP - 49

EP - 62

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 1

ER -

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature

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