Faculty, Staff and Student Publications
Language
English
Publication Date
8-16-2025
Journal
Human Molecular Genetics
DOI
10.1093/hmg/ddaf082
PMID
40420380
PMCID
PMC12361114
PubMedCentral® Posted Date
5-27-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Humans, Jumonji Domain-Containing Histone Demethylases, Female, Male, Neurodevelopmental Disorders, Child, F-Box Proteins, Child, Preschool, Adolescent, Haploinsufficiency, Phenotype, Adult, Mutation, DNA-Binding Proteins, DNA, Protein Domains, Infant, Intellectual Disability, Developmental Disabilities, intellectual disability, congenital heart disease, chromatinopathy, clinical genetics, developmental delay
Published Open-Access
yes
Recommended Citation
van Oirsouw, Amber S E; Hadders, Michael A; Koetsier, Martijn; et al., "KDM2B Variants in the CxxC Domain Impair Its DNA-Binding Ability and Cause a Distinct Neurodevelopmental Syndrome" (2025). Faculty, Staff and Student Publications. 5599.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5599
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons