Missense variants in the spectrin repeat domain of DSP are associated with arrhythmogenic cardiomyopathy: A family report and systematic review

Am J Med Genet A. 2020 Oct;182(10):2359-2368. doi: 10.1002/ajmg.a.61799. Epub 2020 Aug 18.


Rare loss of function variants in DSP, which codes for the desmosomal protein desmoplakin, have been implicated in dilated and arrhythmogenic right ventricular cardiomyopathies. We present a family with arrhythmogenic cardiomyopathy associated with a novel missense variant in DSP (NM_004415.4): c.877G>A, p.(Glu293Lys). The phenotype is characterized by predominant involvement of the left ventricle with systolic dysfunction, fibrosis, and life-threatening arrhythmias. We performed a systematic review of literature collecting all cardiomyopathy cases with rare missense variants in DSP. We demonstrate that the distribution of missense variants across the protein domains in cardiomyopathy cases differs from that in gnomAD (p = .04), with a case enrichment of rare missense variants in the spectrin repeat domain (36/78 [46%] in cases vs. 449/1495 [30%] in gnomAD; p = .004). Our findings highlight the predominance of cardiac arrhythmia and left ventricular involvement in desmoplakin cardiomyopathy and pinpoint to a potential mutation hotspot in DSP thereby facilitating missense variant interpretation in the diagnostic setting.

Keywords: cardiomyopathy; desmoplakin; missense variant; spectrin repeat domain; sudden cardiac death.

Publication types

  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / pathology
  • Arrhythmogenic Right Ventricular Dysplasia / genetics*
  • Arrhythmogenic Right Ventricular Dysplasia / pathology
  • Desmoplakins / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Heart Ventricles / pathology
  • Humans
  • Male
  • Mutation, Missense / genetics
  • Phenotype


  • DSP protein, human
  • Desmoplakins

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