ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

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.