biostudies-literaturevan Oirsouw ASEUS NINDSDutch Research Council (NWO)Wilhelmina Children's Hospital Research FundNINDS NIH HHSStichting 12qZonMwWellcome TrustWilhelmina Children’s Hospital Research Fund1353-1367https://www.ebi.ac.uk/biostudies/studies/S-EPMC12361114biostudies-literatureUnknown34(16)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 Human molecular geneticsKDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome.PMC1236111409150172110002K08NS117891-01WKZ onderzoeksfonds 2020-2021K08 NS117891Dunnington LBeil AAlders MBarakat TSOegema RAssia Batzir NPeters EDJMaya IMcEntagart MGenetti CAJanuel LKoeleman BPCBaralle DBonnet-Dupeyron MNPujalte MBoone PMBouman AHadders MAWalker SNorthrup HRichardson KJoshi AKoetsier MIsidor BFarach LSLahiri Nvan Oirsouw ASECarere DALee KNvan Jaarsveld RHCogne BfalseKDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome.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 2025-01-01T00:00:00Z2025 Aug2026-05-29T17:08:34.999Z2026-04-08T05:28:00.657ZS-EPMC123611144042038010.1093/hmg/ddaf082