ClinGen Dosage Sensitivity Curation Page

DMD

  • Curation Status: Complete

Location Information

  • Xp21.2-p21.1
  • GRCh37/hg19 chrX: 31,137,345-33,357,726
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chrX: 31,119,219-33,339,609
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000023.10) (NC_000023.11)

Haploinsufficiency phenotype comments:

Whole gene and intragenic DMD deletions, as well as intragenic duplications and sequence-level mutations, have been identified in a spectrum of muscle diseases known as the dystrophinopathies; Duchenne muscular dystrophy (DMD), Becker Muscular Dystrophy (BMD), and Cardiomyopathy, dilated, 3B (CMD3B). Resultant phenotypes are best correlated with the degree of dystrophin protein expression. In general, mutations leading to a complete loss-of-function cause DMD while those that reduce dystrophin protein levels and/or function lead to BMD. These genotype;phenotype correlations were confirmed by PMID 16770791: Aartsma-Rus et al., 2006, in a review of over 4700 reported mutations in the Leiden Duchenne Muscular Dystrophy Database. Mutations of the muscle promoter and first exon of the DMD gene that affect cardiac-specific dystrophin expression lead to CMD3B. Penetrance in carrier females varies and may depend on mutation type and pattern of X-chromosome inactivation. Carrier females may manifest a dilated cardiomyopathy phenotype; see GeneReviews for additional information.

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

Triplosensitivity phenotype comment:

While whole gene duplications have not been reported in association with clinical phenotypes, intragenic DMD duplications and triplications have been reported in patients with DMD and BMD, presumably by a loss-of-function-type mechanism.

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.