1. Variants in CUL4B are Associated with Cerebral Malformations
- Author
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Vulto-van Silfhout, Anneke T, Nakagawa, Tadashi, Bahi-Buisson, Nadia, Haas, Stefan A, Hu, Hao, Bienek, Melanie, Vissers, Lisenka ELM, Gilissen, Christian, Tzschach, Andreas, Busche, Andreas, Müsebeck, Jörg, Rump, Patrick, Mathijssen, Inge B, Avela, Kristiina, Somer, Mirja, Doagu, Fatma, Philips, Anju K, Rauch, Anita, Baumer, Alessandra, Voesenek, Krysta, Poirier, Karine, Vigneron, Jacqueline, Amram, Daniel, Odent, Sylvie, Nawara, Magdalena, Obersztyn, Ewa, Lenart, Jacek, Charzewska, Agnieszka, Lebrun, Nicolas, Fischer, Ute, Nillesen, Willy M, Yntema, Helger G, Järvelä, Irma, Ropers, Hans-Hilger, de Vries, Bert BA, Brunner, Han G, van Bokhoven, Hans, Raymond, F Lucy, Willemsen, Michèl AAP, Chelly, Jamel, Xiong, Yue, Barkovich, A James, Kalscheuer, Vera M, Kleefstra, Tjitske, and de Brouwer, Arjan PM
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Clinical Research ,Intellectual and Developmental Disabilities (IDD) ,Brain Disorders ,Neurosciences ,Pediatric ,Rare Diseases ,Congenital Structural Anomalies ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adolescent ,Adult ,Brain ,Cell Cycle Proteins ,Cells ,Cultured ,Child ,Child ,Preschool ,Cullin Proteins ,Genetic Association Studies ,HEK293 Cells ,Humans ,Infant ,Male ,Malformations of Cortical Development ,Mental Retardation ,X-Linked ,Middle Aged ,Nerve Tissue Proteins ,Pedigree ,Sequence Analysis ,DNA ,Young Adult ,CUL4B ,WDR62 ,cortical dysplasia ,hydrocephalus ,intellectual disability ,mutation ,Clinical Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
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.
- Published
- 2015