Submission Details

DSP was evaluated for autosomal dominant dilated cardiomyopathy (DCM). Human genetic evidence supporting this gene-disease relationship includes case-level data, segregation data, and case-control data. There are multiple families with DCM with truncating variants in DSP segregating in the family in the literature. Only case-level and segregation data was scored for DCM and there was no evidence suggesting the probands and/or family members met ARVC TFC. Case-control evidence shows that DSP variants are over-represented in cases versus controls (Mazzarotto et al, 2020, PMID 31983221). Additional human genetic evidence is available in the literature that was not included in the curation scoring as the maximum score for genetic evidence was reached. In addition, this gene-disease association is supported by experimental evidence, including expression data and animal models. DSP has been shown to be expressed in the heart, and also one of the intercalated disc components highly related to LV function, providing evidence of protein interaction (Kazerounian et al, 2002, PMID: 12366696; Ortega et al, 2017, PMID: 28934278). DSP KO mice exhibit a biventricular cardiomyopathy, although it is particularly arrhythmic with sudden death (Lyon et al, 2014, PMID: 24108106). In summary, there is strong evidence to support the relationship between DSP and autosomal dominant DCM. Of note, DSP has also been curated by the ARVC Gene Curation Expert Panel for arrhythmogenic cardiomyopathy with wooly hair and keratoderma (Strong, July 12, 2019), as there are also several families in which individuals meet arrhythmogenic right ventricular cardiomyopathy (ARVC) task force criteria (TFC). Experts in the DCM GCEP encourage clinicians to carefully evaluate for a possibility of an ACM phenotype and treat patients and families with DSP variants accordingly. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on June 12, 2020.