Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.
Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.
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DOI：
10.1016/j.gim.2022.09.006
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发表时间：
2023-01
影响因子：
8.8
通讯作者：
Oegema, Renske
中科院分区：
文献类型：
--
作者：
van Jaarsveld, Richard H.;Reilly, Jack;Cornips, Marie-Claire;Hadders, Michael A.;Agolini, Emanuele;Ahimaz, Priyanka;Anyane-Yeboa, Kwame;Bellanger, Severine Audebert;van Binsbergen, Ellen;van den Boogaard, Marie-Jose;Brischoux-Boucher, Elise;Caylor, Raymond C.;Ciolfi, Andrea;van Essen, Ton A. J.;Fontana, Paolo;Hopman, Saskia;Iascone, Maria;Javier, Margaret M.;Kamsteeg, Erik-Jan;Kerkhof, Jennifer;Kido, Jun;Kim, Hyung-Goo;Kleefstra, Tjitske;Lonardo, Fortunato;Lai, Abbe;Lev, Dorit;Levy, Michael A.;Lewis, M. E. Suzanne;Lichty, Angie;Mannens, Marcel M. A. M.;Matsumoto, Naomichi;Maya, Idit;McConkey, Haley;Megarbane, Andre;Michaud, Vincent;Miele, Evelina;Niceta, Marcello;Novelli, Antonio;Onesimo, Roberta;Pfundt, Rolph;Popp, Bernt;Prijoles, Eloise;Relator, Raissa;Redon, Sylvia;Rots, Dmitrijs;Rouault, Karen;Saida, Ken;Schieving, Jolanda;Tartaglia, Marco;Tenconi, Romano;Uguen, Kevin;Verbeek, Nienke;Walsh, Christopher A.;Yosovich, Keren;Yuskaitis, Christopher J.;Zampino, Giuseppe;Sadikovic, Bekim;Alders, Marielle;Oegema, Renske
参与表观遗传机制的基因致病性变异是神经发育障碍（ndd）的新原因。赖氨酸去甲基化酶2B （KDM2B）编码表观遗传调节因子，小鼠模型表明其在发育过程中发挥重要作用。我们着手确定KDM2B变体是否与NDD相关。通过国际合作，我们收集了杂合KDM2B变异个体的数据。我们将甲基化阵列应用于外周血DNA样本，以确定KDM2B相关的表观遗传特征。我们共招募了27名携带KDM2B杂合变异体的个体。我们提供了证据，包括一个共同的表观遗传特征，以支持15个KDM2B变异的致病分类，并确定CxxC结构域是突变热点。功能丧失和cxxc结构域错义变体都具有特定的子签名。此外，在多个个体的双重分子诊断背景下确定了KDM2B的特征。我们的努力产生了一个由21个杂合（可能）致病变异个体组成的队列。本队列中存在发育迟缓和/或智力残疾的个体；自闭症;注意缺陷障碍/注意缺陷多动障碍；先天性器官异常，主要是心脏、眼睛和泌尿生殖系统；还有轻微的面部畸形。KDM2B的致病性杂合变异体与NDD和在外周血中可检测到的特定表观遗传特征相关。
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. 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. 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. Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.
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