ClinGen Dosage Sensitivity Curation Page

CASK

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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).

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.