ClinGen Dosage Sensitivity Curation Page

DCX

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

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.