DSG2 was originally for DCM by the ClinGen DCM GCEP on 08/07/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 03/27/2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.
Human genetic evidence supporting this gene-disease relationship includes two published definitive DCM cases with truncating variants in DSG2 (Garcia-Pavia et al, 2011, PMID: 21859740; Sumida et al, 2024, PMID: 39706847). The first was published by Garcia-Pavia et al. Of note, this person had limited ECG/arrhythmia phenotyping. In the second publication, , Sumida et al. present 4 families with a DSG2 truncation. Importantly, of these four families, two families were not scored due to combination phenotypes (ARVC, HCM), and one due to a second pathogenic variant. Therefore, only 1.5 additional points were added since the initial curation from one DSG2 DCM patient. Multiple other published variants have population frequencies which exclude them from scoring, as they are observed at a frequency higher than would be expected to have a pathogenic effect.
In addition, this gene-disease association is supported by experimental evidence from postnatal DCM hearts showing reduced DSG2 signal in myocardium and other intercalated disc proteins were normal(Kessler et al, 2017, PMID: 28764973). Immunohistochemical and electron microscopy evidence available since the initial curation did not reach the level of significance (Sumida et al, 2024, PMID: 39706847).
In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of DSG2 with AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 03/27/2025 (SOP Version 10).
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