ClinGen Dosage Sensitivity Curation Page

CASK

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21954287 Moog et al (2011) report female patients with intellectual disability, hypotonia, microcephaly, optic nerve hypoplasia, dysmorphic features, and diffuse brainstem and cerebellar hypoplasia who had loss of function mutations in CASK. Mutations include 3 intragenic deletions, 4 nonsense, 1 frameshift, and one intragenic duplications involving exons 2-8. Additionally, some patients had larger deletions or duplications involving other genes, missense and splicing mutations. All mutations were found to be de novo if parents were available for testing. Most patients had random X-inactivation.
21735175 Hayashi et al (2012) report female patients with intellectual disability, microcephaly, dysmorphic features, and pontocerebellar hypoplasia. Mutations include 3 nonsense, 1 frameshift, 2 invariant splice site, 2 intragenic duplications resulting in aberrant transcripts, and two large deletions (1.1 and 3 Mb). All mutations were found to be de novo if parents were available for testing.
22452838 Burglen et al (2012) report female patients with intellectual disability and pontocerebellar hypoplasia who had de novo mutations including 1 focal deletion, 5 nonsense, 1 frameshift, and 3 invariant splice site). They also report a very severely affected male with a splice site mutation and a mildly affected male who had a mosaic nonsense mutation (both de novo).

Haploinsufficiency phenotype comments:

In addition to the loss of function mutations described above that are associated with mental retardation and microcephaly with pontine and cerebellar hypoplasia in females (OMIM 300749), missense mutations that may retain some function have been described in male patients with FG syndrome 4 and mental retardation with or without nystagmus, OMIM 300422 - see PMIDs: 19165920, 19200522, 19377476, 20029458.

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.