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

被引：12

作者：

van Jaarsveld, Richard H. ^{[1
]}

Reilly, Jack ^{[2
]}

Cornips, Marie-Claire ^{[1
]}

Hadders, Michael A. ^{[3
,4
]}

Agolini, Emanuele ^{[5
]}

Ahimaz, Priyanka ^{[6
]}

Anyane-Yeboa, Kwame ^{[6
]}

Bellanger, Severine Audebert ^{[7
]}

van Binsbergen, Ellen ^{[1
]}

van den Boogaard, Marie-Jose ^{[1
]}

Brischoux-Boucher, Elise ^{[8
]}

Caylor, Raymond C. ^{[9
]}

Ciolfi, Andrea ^{[10
]}

van Essen, Ton A. J. ^{[11
]}

Fontana, Paolo ^{[12
]}

Hopman, Saskia ^{[1
]}

Iascone, Maria ^{[13
]}

Javier, Margaret M. ^{[14
]}

Kamsteeg, Erik-Jan ^{[15
]}

Kerkhof, Jennifer ^{[16
]}

Kido, Jun ^{[17
]}

Kim, Hyung-Goo ^{[18
]}

Kleefstra, Tjitske ^{[15
]}

Lonardo, Fortunato ^{[12
]}

Lai, Abbe ^{[19
,20
,21
]}

Lev, Dorit ^{[22
]}

Levy, Michael A. ^{[16
]}

Lewis, M. E. Suzanne ^{[14
]}

Lichty, Angie ^{[9
]}

Mannens, Marcel M. A. M. ^{[23
]}

Matsumoto, Naomichi ^{[24
]}

Maya, Idit ^{[25
,26
]}

McConkey, Haley ^{[2
,16
]}

Megarbane, Andre ^{[27
,28
]}

Michaud, Vincent ^{[29
]}

Miele, Evelina ^{[30
]}

Niceta, Marcello ^{[10
]}

Novelli, Antonio ^{[5
]}

Onesimo, Roberta ^{[31
]}

Pfundt, Rolph ^{[15
]}

Popp, Bernt ^{[32
,33
]}

Prijoles, Eloise ^{[9
]}

Relator, Raissa ^{[16
]}

Redon, Sylvia ^{[7
,34
]}

Rots, Dmitrijs ^{[15
]}

Rouault, Karen ^{[7
,34
]}

Saida, Ken ^{[24
]}

Schieving, Jolanda ^{[35
]}

Tartaglia, Marco ^{[10
]}

Tenconi, Romano ^{[36
]}

机构：

[1] Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands

[2] Western Univ, Dept Pathol & Lab Med, London, ON, Canada

[3] Univ Utrecht, Univ Med Ctr Utrecht, Oncode Inst, Utrecht, Netherlands

[4] Univ Med Ctr Utrecht, Univ Utrecht, Ctr Mol Med, Utrecht, Netherlands

[5] IRCCS, Bambino Gesis Children Hosp, Translat Cytogen Res Unit, Lab Med Genet, I-00165 Rome, Italy

[6] Columbia Univ, Dept Pediat, Div Clin Genet, New York, NY USA

[7] Ctr Hosp Reg Univ Brest, Serv Genet Med & Biol Reprod, Brest, France

[8] Univ Franche Comte, Ctr Genet Humaine, CHU Besancon, Besancon, France

[9] Greenwood Genet Ctr, Greenwood, SC USA

[10] IRCCS, Bambino Gesis Childrens Hosp, Genet & Rare Dis Res Div, Rome, Italy

[11] Univ Groningen, Univ Med Ctr Groningen, Dept Med Genet, Groningen, Netherlands

[12] AORN San Pio, Med Genet Unit, Benevento, Italy

[13] ASST Papa Giovanni XXIII, Lab Genet Med, Bergamo, Italy

[14] Univ British Columbia, BC Childrens Hosp Res Inst, Dept Med Genet, Vancouver, BC, Canada

[15] Radboud Univ Nijmegen, Department Human Genet, Med Ctr, Nijmegen, Netherlands

[16] London Hlth Sci Ctr, Verspeeten Clin Genome Ctr, London, ON, Canada

[17] Kumamoto Univ, Dept Pediat, Fac Life Sci, Kumamoto, Japan

[18] Hamad Bin Khalifa Univ, Qatar Biomed Res Inst, Neurol Disorders Res Ctr, Doha, Qatar

[19] Harvard Med Sch, Boston Childrens Hosp, Div Epilepsy & Clin Neurophysiol, Boston, MA USA

[20] Harvard Med Sch, Boston Childrens Hosp, Epilepsy Genet Program, Boston, MA USA

[21] Harvard Med Sch, Boston Childrens Hosp, Genet & Genom, Boston, MA USA

[22] Wolfson Med Ctr, Rina Mor Inst Med Genet, Holon, Israel

[23] Univ Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam Reprod & Dev Res Inst, Amsterdam, Netherlands

[24] Yokohama City Univ, Dept Human Genet, Grad Sch Med, Yokohama, Japan

[25] Beilinson Med Ctr, Raphael Recanati Genet Inst, Rabin Med Ctr, Petah Tiqwa, Israel

[26] Tel Aviv Univ, Fac Med, Tel Aviv, Israel

[27] Lebanese Amer Univ, Gilbert & Rose Marie Chagoury Sch Med, Dept Human Genet, Beirut, Lebanon

[28] Inst Jerome Lejeune, Paris, France

[29] CHU Bordeaux, Dept Med Genet, Bordeaux, France

[30] IRCCS, Bambino Gesu Childrens Hosp, Sci Inst Res Hospitalizat & Healthcare, Dept Pediat Hematol & Oncol & Cellular & Gene The, Rome, Italy

[31] Fdn Policlin Univ A Gemelli IRCCS, Ctr Rare Dis & Congenital Defects, Rome, Italy

[32] Univ Leipzig, Inst Human Genet, Med Ctr, Leipzig, Germany

[33] Charite Univ Med Berlin, Berlin Inst Hlth, Ctr Funct Genom, Berlin, Germany

[34] Univ Brest, INSERM, EFS, UMR 1078,GGB, Brest, France

[35] Radboud Univ Nijmegen, Dept Pediat Neurol, Med Ctr, Nijmegen, Netherlands

[36] Univ Padua, Dept Women & Childrens Hlth, Clin Genet Unit, Padua, Italy

[37] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA

[38] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA USA

[39] Edith Wolfson Med Ctr, Mol Genet Lab, Holon, Israel

[40] Univ Cattolica Sacro Cuore, Fac Med & Surg, Rome, Italy

来源：

GENETICS IN MEDICINE | 2023年 / 25卷 / 01期

关键词：

Human Genetics; KDM2B; MDEMs; Methylation signatures; Neurodevelopmental disorders; HISTONE DEMETHYLASE KDM2B; PRC1; COMPLEX; CPG ISLANDS; RECRUITMENT; SENESCENCE; EXPRESSION; DIAGNOSIS; PROTEIN; FBXL10; GENES;

D O I：

10.1016/j.gim.2022.09.006

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 hetero-zygous 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.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

引用

页码：49 / 62

页数：14

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