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Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature
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 va...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825659/ https://www.ncbi.nlm.nih.gov/pubmed/36322151 http://dx.doi.org/10.1016/j.gim.2022.09.006 |
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author | van Jaarsveld, Richard H. Reilly, Jack Cornips, Marie-Claire Hadders, Michael A. Agolini, Emanuele Ahimaz, Priyanka Anyane-Yeboa, Kwame Audebert Bellanger, Severine 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, Mariëlle Oegema, Renske |
author_facet | van Jaarsveld, Richard H. Reilly, Jack Cornips, Marie-Claire Hadders, Michael A. Agolini, Emanuele Ahimaz, Priyanka Anyane-Yeboa, Kwame Audebert Bellanger, Severine 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, Mariëlle Oegema, Renske |
author_sort | van Jaarsveld, Richard H. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9825659 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-98256592023-01-08 Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature van Jaarsveld, Richard H. Reilly, Jack Cornips, Marie-Claire Hadders, Michael A. Agolini, Emanuele Ahimaz, Priyanka Anyane-Yeboa, Kwame Audebert Bellanger, Severine 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, Mariëlle Oegema, Renske Genet Med Article 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. 2022-11-01 /pmc/articles/PMC9825659/ /pubmed/36322151 http://dx.doi.org/10.1016/j.gim.2022.09.006 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article van Jaarsveld, Richard H. Reilly, Jack Cornips, Marie-Claire Hadders, Michael A. Agolini, Emanuele Ahimaz, Priyanka Anyane-Yeboa, Kwame Audebert Bellanger, Severine 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, Mariëlle Oegema, Renske Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature |
title | Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature |
title_full | Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature |
title_fullStr | Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature |
title_full_unstemmed | Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature |
title_short | Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature |
title_sort | delineation of a kdm2b-related neurodevelopmental disorder and its associated dna methylation signature |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825659/ https://www.ncbi.nlm.nih.gov/pubmed/36322151 http://dx.doi.org/10.1016/j.gim.2022.09.006 |
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