ClinGen Dosage Sensitivity Curation Page

HCCS

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17033964 Wimplinger (2006): A report of two sisters with microphthalmia with linear skin defects (MLS) syndrome who had a deletion of exons 1-3 in HCCS. The deletion also included two exons that the authors thought were the 5' untranslated exons 1a and 1b of the MID1 gene. However, subsequent analysis by Qidwai et al (PMID: 20503342) showed that MID1 was not involved. This deletion was inherited from the mother who had no ocular findings; skin findings were not ruled out. Another patient with MLS syndrome was found to have a de novo nonsense mutation resulting in a protein that lacked the C-terminal portion and failed to localize to the mitochondria. A third patient with MLS syndrome had a de novo missense mutation that did localize to the mitochondria. Yeast complementation studies for both point mutations showed failure to restore growth.

Haploinsufficiency phenotype comments:

The majority of patients with MLS syndrome have cytogenetic abnormalities which usually include deletion at Xp22.2. Morleo et al (2005, PMID: 16059943) identified the minimal critical region to be 610 kb that includes MID1, HCCS, and ARHGAP6. The mutations reported above, plus an additional female patient reported by Wimplinger (2007, PMID: 17893649) who had bilateral microphthalmia and scleral cornea and a missense mutation in HCCS, have led to the conclusion that loss of function of HCCS is the cause of MLS syndrome in females. HCCS mutations are thought to be lethal in males. See Gene Reviews.

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.