ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000018.9) (NC_000018.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17186466 Heuser et al. (2006), describe a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (AVRD/C). This patient was found to be a heterozygous carrier of a novel splice-site mutation in intron 5 (c.631-2ArG) of DSC2, which is predicted to lead to the production of a premature stop codon. Quantification of DSC2 expression in heart tissue demonstrated that the patient had a significant decrease in the mutant DSC2 transcript, with approximately 50% of the normal transcript remaining, while western blot analysis showed a decrease in the total DSC2 protein level. Based on these results the authors suggest that nonsense-mediated mRNA decay and haploinsufficiency are likely contributing to the disease mechanism in this patient.
17033975 Syrris et al. (2006) describe four proband with mutations in DSC2 presenting with AVRD/C. In Family A, a single nucleotide deletion in exon 10 resulting in a frameshift mutation (M477fsX480) in the proband and her mother was predicted to result in premature termination. In families B, C, and D, the probands had a 2 bp insertion in exon 17 ((2687_2688insGA), also predicted to result in premature termination because of frameshift. Families B, C, and D all had a positive family history of sudden cardiac death, although there appears to be incomplete penetrance in mutation carriers. The authors speculate that the deletion mutation in Family A results in haploinsufficiency; however there are no functional studies that support this association. The functional result of the 2 bp insertion in the other families is more difficult to determine without functional studies, since DSC2 produces two transcripts due to alternative splicing in exon 16.
21062920 Gehmlich et al. (2010) used transient transfection assays to study the function and expression of missense and frameshift mutations in DSC2. The authors conclude that the missense mutations result in a decrease of available DCS2 mature functional protein, and this decrease, rather than a dominant negative effect, is responsible for features of AVRD/C. The functional studies on the frameshift mutation did not show a decrease in the amount of mature functional protein, but did show a decreased affinity to its binding partner plakoglobin (PG). The authors note that in vivo studies are still required to accurately assess the functional effects of mutations.

Haploinsufficiency phenotype comments:

DSC2 encodes the desmosomal cadherin, desmocollin 2. Sequence-level variants in DSC2 are associated with arrhythmogenic right ventricular cardiomyopathy 11 (AVRC) (OMIM: 610476), a genetically heterogeneous cardiovascular disorder characterized by fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmia, and an increased risk of premature sudden cardiac death. A large number (n>50) of DSC2 mutations have been reported in the literature, the majority of which are missense mutations. Several mutations that may confer a loss-of-function have also been reported, including splice-site, intragenic deletions/duplications, and nonsense mutations, which have been observed in association with both autosomal dominant (PMID: 17186466 and 17033975) and autosomal recessive (PMID: 20400443, 19863551, 24793512, 23863954) forms of AVRC. Incomplete penetrance for some DSC2 variants has also been observed. Although more than two independent publications with loss-of-function-type variants provides evidence in support of DSC2 haploinsufficiency, due to the variable inheritance patterns, mutational spectrum, and lack of reports of whole gene deletions, the haploinsufficiency score is a 2.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there is no evidence that supports the triplosensitivity of this gene.