Variants inCUL4Bare Associated with Cerebral Malformations

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Abstract

Variants incullin 4B(CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants inCUL4B. 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 inCUL4B.

This study reports 25 patients from eleven families with variants in CUL4B, known to cause X-linked intellectual disability. Nine different novel variants were identified and pathogenicity of all non-truncating variants was confirmed. Neuroimaging data, available for 15 patients showed the presence of cerebral malformations comprising malformations of cortical development, ventriculomegaly and diminished white matter volume in ten patients.

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