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 loss of function variants in CUL4B, including one frameshift, two nonsense, and two splice variants. Carrier females were unaffected.
17273978	Zou (2007) reported a large family with X-linked intellectual disability. They identified a nonsense variant in CUL4B (R388X) in seven affected males and six carrier females. All female carriers were phenotypically normal and had skewed X-inactivation.
22182342	Ravn (2011): A report of monozygotic male twins with intellectual disability, seizures, short stature, truncal obesity and dysmorphic features who had a 28 kb deletion involving only CUL4B. The deletion was inherited from a normal mother who had skewed X-inactivation.
26350204	In a cohort of 986 individuals with intellectual disability Grozeva et al (2015) identified 5 loss of function variants in CUL4B including 1 frameshift, 1 splice-site, and 3 nonsense variants.

Haploinsufficiency phenotype comments:

Loss of function mutations in CUL4B are now considered to be the cause of Cabezas syndrome, a form of syndromic X-linked intellectual disability. Additional features frequently include speech impairment, short stature, hypogonadism, central obesity and abnormal gait.

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.