CUL4B

• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: MENTAL RETARDATION, X-LINKED, SYNDROMIC, CABEZAS TYPE; MRXSC

Evidence for haploinsufficiency phenotype

PubMed ID	Description
17236139	Tarpey (2007): A report of five families with intellectual disability in males who were found to have truncating mutations in CUL4B, include one frameshift, two nonsense, and two splice mutations. Carrier females were unaffected.
17273978	Zou (2007): A report of a large family with intellectual disability, short stature, and dysmorphic features in males. All affected individuals had a nonsense mutation. Carrier females were phenotypically normal and had skewed X-inactivation.
22182342	Ravn (2011): A report of monozygotic male twins with intellectual disability, seizures, short stature, and congenital anomalies who had a focal deletion involving only CUL4B. The deletion was inherited from a normal mother who had skewed X-inactivation.

Haploinsufficiency phenotype comments:

Loss of function mutations in CUL4B are now considered to be the cause of Cabeza's syndrome, a form of syndrome X-linked mental retardation. Additional reports of mutations include PMID: 20014135, 20002452.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

• Triplosensitivity score: 0
• Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.