Journal
HUMAN MUTATION
Volume 36, Issue 1, Pages 106-117Publisher
WILEY
DOI: 10.1002/humu.22718
Keywords
CUL4B; WDR62; cortical dysplasia; hydrocephalus; intellectual disability; mutation
Categories
Funding
- European Commission (GENCODYS grant) [241995]
- Dutch Organisation for Health Research and Development (ZON-MW grant) [917-86-319, 907-00-365]
- Dutch Brain Foundation [2009(2)-81]
- Van Leersum Fund
- German Ministry of Education and Research through the MRNET
- Max Planck Innovation Funds
- Sigrid Juselius Foundation, Helsinki, Finland
- NIH [GM067113]
- Action Medical Research and NIHR Biomedical Research Centre, UK
- Polish Ministry of Science and Higher Education [NN407133739]
- Grants-in-Aid for Scientific Research [25891003] Funding Source: KAKEN
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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.
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