A new CUL4B variant associated with a mild phenotype and an exceptional pattern of leukoencephalopathy

Cabezas type of X-linked syndromic intellectual disability (MRXSC; MIM300354) is a rare X-linked recessive intellectual disability characterized primarily by intellectual disability, short stature, hypogonadism, and gait abnormalities. It is caused by a wide spectrum of hemizygous variants in CUL4B. In a 10-year-old boy with an exceptional leukoencephalopathy pattern, we identified a new missense variant p.Leu329Gln in CUL4B using “Mendeliome” sequencing. However, his phenotype does not include the severe characteristics currently known for MRXSC. We discuss the divergent phenotype and propose a potential connection between the different CUL4B variants and corresponding phenotypes in the context of the current literature as well as 3D homology modeling.