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ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000018.9) (NC_000018.10)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
21397041 Lahtinen et al. (2011) identified a proband with ARVC who had a novel 3059_3062delAGAG frameshift mutation leading to abolishing 99 carboxy-terminal amino acids of desmoglein-2. This mutation was found in four additional family members: two of whom met minor criteria for first-degree family members, one had minor repolarization abnormalities, and the fourth was unaffected. A screen for this mutation in the control samples revealed one carrier who then was found to have a conduction defect. Since the immunoreactive signal for desmoglein-2 was reduced by over 50%, a dominant-negative effect for the mutation was suggested as a possibility.
26296472 Zhang et al. (2015) obtained DNA from post-mortem heart tissues, 25 patients had ARVC as a cause of death while the other 25 had sudden unexplained death. Two novel mutations in DSG2 were identified in each group. A frameshift insertion c.3075_3076insC (S1026Q fsX12) and a missense c.2032G>A (G678R) mutation was found in the ARVC group. In the samples from patients with sudden unexplained death, the missense mutations were c.2686G>A (E896K) and c.2573C>T (A858V). None of these variants was found in 96 control samples. No commentary as to possible mutation mechanism was included.
16773573 Awad et al (2006) identified four patients with ARVD/C with mutations in DSG2. One proband had two mutations in trans, a missense c.143G>A (R48H) on his paternal allele and a c.915G>A change resulting in a premature termination codon, W305X, in exon 8 of his maternal allele. Of note, his 77-year-old mother was found to carry the same nonsense mutation, but was unaffected based upon extensive clinical assessments. His 24 year-old sister also carries the W305 mutation and is believed to be unaffected. His father who presumably passed on the R48H mutation died due to non-cardiac issues at age 74 and was never tested. The remaining three probands in this study had a single, heterozygous missense mutation each: c.134G>A (R45Q), c.1517G>A (C506Y), and c.2431G>T (G811C). Of note, the mother of the proband with R45Q and the mother of the proband with G811C were both found to be carriers of their respective familial mutation and were determined to be unaffected after extensive cardiac assessments. Discussion regarding mutational mechanism included the possibility of both haploinsufficiency and dominant-negative as possible mechanisms.

Haploinsufficiency phenotype comments:

Desmoglein-2 (DSG2) is a member of the desmoglein family and is expressed in myocardium. DSG2 is an essential component of the desmosome so mutations of this gene disrupt the proper organization of desmosomal junctions. Mutations of DSG2 and other desmosomal genes have been demonstrated to be associated with arrhythmogenic right ventricular dilatation/cardiomyopathy (ARVD/C), but the phenotype is widely variable ranging from individuals who meet strict diagnostic criteria to those who are asymptomatic and identified in control populations. Some affected patients have compound heterozygous mutations. So variants in DSG2 might be susceptibility variants, rather than pathogenic variants. Also, digenic, homozygous, and compound heterozygous inheritance has been suggested. While a few protein truncating mutations have been described, the mechanism by which these mutations cause disease has not been clearly determined and no patients with complete gene deletions and ARVD/C have been reported.

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