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Missense variants in the spectrin repeat domain of DSP are associated with arrhythmogenic cardiomyopathy: A family report and systematic review
Author(s) -
Grondin Steffany,
Wazirian AvedisChrist,
Jorda Paloma,
Terrone Donato G.,
Gag Johannie,
Robb Laura,
Amyot Julie,
Rivard Lena,
Pagé Sylvain,
Talajic Mario,
CadrinTourigny Julia,
Tadros Rafik
Publication year - 2020
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61799
Subject(s) - missense mutation , desmoplakin , cardiomyopathy , dilated cardiomyopathy , medicine , phenotype , cardiology , genetics , biology , heart failure , gene
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.