ClinGen Dosage Sensitivity Curation Page

PCDH19

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
18469813 Dibbens et al (2008) report mutations in families with epilepsy and mental retardation limited to females (EFMR) with no affected males. Two nonsense mutations (shown to be subject to nonsense-mediated decay), three frameshift, and 2 missense changes were reported. X-inactivation was random for all affected females. Mutations were either de novo or inherited from healthy fathers. Cellular inference between PCDH19+ and PCDH19- cells is proposed as the model of disease.
19214208 Depienne et al (2009) report a male patient with Dravet syndrome who is negative for SCN1A mutation with a de novo 890 deletion of PCDH19. FISH on fibroblasts showed 53% of cells were normal. This mosaicism would be consistent with the cellular inference model. Additionally, 3 nonsense, 2 frameshift, and 4 missense mutations were found in females with Dravet-like symptoms. If inheritance was known, mutations were either de novo, inherited from a normal father, or inherited from an affected mother.
23712037 Higurashi et al (2013) tested females with early-onset seizures and found 17 mutations, including 3 large deletions, 4 nonsense, and 3 frameshift. One nonsense mutation was inherited from a healthy father but was also present in two unaffected sisters (all three females had random X-inactivation).

Haploinsufficiency phenotype comments:

In addition to the three papers listed above, mutations in PCDH19 are reported in the following papers: PMIDs 23334464, 22949144, 22848613, 22633638, 22091964, 21053371, 20830798, 20713952, and 19752159. X-inactivation patterns may vary clinical outcome.

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.