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

Research output: Contribution to journalArticleAcademicpeer-review


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 languageEnglish
Pages (from-to)49-62
Number of pages14
JournalGenetics in medicine
Issue number1
Early online date2022
Publication statusPublished - Jan 2023


  • Human Genetics
  • KDM2B
  • MDEMs
  • Methylation signatures
  • Neurodevelopmental disorders

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