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KDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome

van Oirsouw, ASE; Hadders, MA; Koetsier, M; Peters, EDJ; Assia Batzir, N; Barakat, TS; Baralle, D; Beil, A; Bonnet-Dupeyron, M-N; Boone, PM; et al. van Oirsouw, ASE; Hadders, MA; Koetsier, M; Peters, EDJ; Assia Batzir, N; Barakat, TS; Baralle, D; Beil, A; Bonnet-Dupeyron, M-N; Boone, PM; Bouman, A; Carere, DA; Cogne, B; Dunnington, L; Farach, LS; Genetti, CA; Isidor, B; Januel, L; Joshi, A; Lahiri, N; Lee, KN; Maya, I; McEntagart, M; Northrup, H; Pujalte, M; Richardson, K; Walker, S; Koeleman, BPC; Alders, M; van Jaarsveld, RH; Oegema, R (2025) KDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome. Human Molecular Genetics. ISSN 0964-6906 https://doi.org/10.1093/hmg/ddaf082
SGUL Authors: Lahiri, Nayana

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Abstract

Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants’ effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the KDM2B-CxxC cohort is more extensive as compared to that of individuals with KDM2B haploinsufficiency. All individuals with CxxC variants presented with developmental delay, mainly in the speech and motor domain, in addition to variable intellectual disability and mild facial dysmorphism. Congenital heart defects were observed in up to 78% of individuals, with additional common findings including musculoskeletal, ophthalmological, and urogenital anomalies, as well as behavioral challenges and feeding difficulties. Functional assays revealed that while mutant KDM2B protein with CxxC variants can be expressed in vitro, its DNA-binding ability is significantly reduced compared to wildtype. This study shows that KDM2B CxxC variants cause a distinct neurodevelopmental syndrome, possibly through a molecular mechanism different from haploinsufficiency.

Item Type: Article
Additional Information: © The Author(s) 2025. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical, Biomedical and Allied Health Education (IMBE)
Journal or Publication Title: Human Molecular Genetics
ISSN: 0964-6906
Language: en
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDWilhelmina Children’s Hospital Research FundUNSPECIFIED
09150172110002Netherlands Organisation for Scientific ResearchUNSPECIFIED
UNSPECIFIEDStichting 12qUNSPECIFIED
K08NS117891-01National Institute of Neurological Disorders and Strokehttps://doi.org/10.13039/100000065
URI: https://openaccess.sgul.ac.uk/id/eprint/117711
Publisher's version: https://doi.org/10.1093/hmg/ddaf082

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