Submission Details

DES was originally evaluated for DCM by ClinGen DCM GCEP on August 14, 2020. Evidence of the association of this gene with DCM was re-evaluated on February 23, 2025. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein.

DES was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 1999 (Li et al., 1999, PMID 10430757).Desmin is the major Intermediate filament that integrates the sarcolemma, Z disk and nuclear membrane in sarcomeres and regulates sarcomeric architecture. Disease-associated desmin variants cause an accumulation of disorganized intracytoplasmic aggregates containing desmin and other cytoskeletal proteins. Human genetic evidence supporting this gene-disease relationship includes case-level data. At least 18 heterozygous variants (including missense, nonsense, splice-site) have been reported in humans with autosomal dominant DCM (Li et al., 1999, PMID 10430757; Miyamoto et al., 2001, PMID 11728149; Taylor et al., 2007, PMID 17325244; Tse et al., 2013, PMID 23300193; Gigli et al., 2019, PMID 31514951; Brodehl et al., 2016, PMID 26724190; van Spaendonck-Zwarts et al., 2013, PMID 23349452; Weihl et al., 2015 PMID 25557463; van Tintelen et al. 2009, PMID 19879535 . This gene-disease relationship has been studied in one large case-control study at the aggregate variant level (Mazzarotto et al., 2020, PMID 31983221). There was no enrichment of rare DES variants in two DCM cohorts compared to ExAC derived controls. In addition, this gene-disease association is supported by animal models, expression studies, and in vitro functional assays (Milner et al., 1999, PMID 10591032; Taylor et al., 2007, PMID 17325244; Tse et al., 2013, PMID 23300193; Brodehl et al., 2016, PMID 26724190. Of note, this gene has also been implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC) and myofibrillar myopathy 1 (MFM1) and has been assessed separately for these distinct phenotypes (Definitive, ARVC, August 25, 2017; Moderate, MFM1, November 9, 2018). In summary, DES is definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was originally approved by the ClinGen Dilated Cardiomyopathy Working Group on August 14th, 2020 (SOP Version 7). This written summary was updated on 02/23/2025 and approved by the DCM GCEP on 05/30/2025.