ClinGen Dosage Sensitivity Curation Page

DCX

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
9489700 Gleeson et al (1998) described 3 unrelated (sporadic) females with subcortical band heterotopia (see loss phenotype description below) with disruption of the DCX gene. Patient 1 has a 2 basepair AG insertion at position 36, resulting in a frameshift and protein termination at amino acid 24. Patient 2 has a 2 basepair CT deletion at position 684, resulting in a frameshift and protein termination at amino acid 240. Patient 3 has a 2 basepair CT deletion at position 691, resulting in a frameshift and protein termination at amino acid 240. Patient 3 was the only one with parental testing, and the mutation is de novo. In the same paper, Gleeson et al also describe 4 families with different missense mutations in the DCX gene. In each of these families, males carrying the mutation have lissencephaly and females with the mutation have subcortical band heterotopia.

Haploinsufficiency phenotype comments:

Males with X-linked lissencephaly (XLIS) caused by mutations in DCX display a phenotype essentially indistinguishable from lissencephaly caused by LIS1 mutations. Affected females heterozygous for DCX mutations show a milder phenotype, presumably representing a mosaic state caused by random inactivation of either the mutant or normal X chromosome. The brains of affected females show a population of neurons that behaves normally and a population that migrates approximately halfway to the cortex and then arrests in the subcortical white matter, producing a band of neurons called subcortical band heterotopia or "doublecortex" (DC). The majority of patients with DC are female, presumably representing mutations in the X-linked locus.

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.