biostudies-literatureVulto-van Silfhout ATSigrid Julius foundationvan Leersum fondsmax planck innovation fundsDutch Brain FoundationFoundation for the National Institutes of HealthGerman ministry of education and researech (MRNET)Polish Ministry of Science and Higher EducationNCI NIH HHSNetherlands Organisation for Health Research and DevelopmentEuropean CommissionWellcome TrustNIGMS NIH HHS106-17https://www.ebi.ac.uk/biostudies/studies/S-EPMC4608231biostudies-literatureUnknown36(1)Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.Human mutationVariants in CUL4B are associated with cerebral malformations.PMC4608231917-86-3192009(2)-81FP6 037627100140GM067113R01 GM067113907-00-365R01 CA068377FP7 241995NN407133739Vissers LEYntema HGAvela KCharzewska ANillesen WMBusche ALenart JPoirier KKleefstra TRaymond FLNawara MMathijssen IBXiong YHaas SAPhilips AKBrunner HGTzschach ALebrun NWillemsen MAChelly JVulto-van Silfhout ATAmram DFischer UBahi-Buisson NKalscheuer VMBaumer ARump PRauch AVigneron JObersztyn EBarkovich AJBienek MRopers HHDoagu FVoesenek Kde Brouwer APGilissen CSomer MJarvela IHu HOdent Svan Bokhoven HNakagawa TMusebeck Jde Vries BBfalseVariants in CUL4B are associated with cerebral malformations.Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.2015-01-01T00:00:00Z2015 Jan2026-05-04T13:50:14.629Z2026-04-24T03:08:51.529ZS-EPMC46082312538519210.1002/humu.22718