Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Genetics in medicine : official journal of the American College of Medical Genetics - 25(2023), 1 vom: 22. Jan., Seite 49-62 |
| Sprache: |
Englisch |
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| Links: |
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| Themen: |
9007-49-2 |
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| Anmerkungen: |
Date Completed 10.01.2023 Date Revised 14.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.gim.2022.09.006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM348361300 |
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| 100 | 1 | |a van Jaarsveld, Richard H |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 10.01.2023 | ||
| 500 | |a Date Revised 14.03.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Human Genetics | |
| 650 | 4 | |a KDM2B | |
| 650 | 4 | |a MDEMs | |
| 650 | 4 | |a Methylation signatures | |
| 650 | 4 | |a Neurodevelopmental disorders | |
| 650 | 7 | |a DNA |2 NLM | |
| 650 | 7 | |a 9007-49-2 |2 NLM | |
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| 700 | 1 | |a Hadders, Michael A |e verfasserin |4 aut | |
| 700 | 1 | |a Agolini, Emanuele |e verfasserin |4 aut | |
| 700 | 1 | |a Ahimaz, Priyanka |e verfasserin |4 aut | |
| 700 | 1 | |a Anyane-Yeboa, Kwame |e verfasserin |4 aut | |
| 700 | 1 | |a Bellanger, Severine Audebert |e verfasserin |4 aut | |
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| 700 | 1 | |a Caylor, Raymond C |e verfasserin |4 aut | |
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| 700 | 1 | |a Kim, Hyung-Goo |e verfasserin |4 aut | |
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