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

Abstract

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.

The genetic architecture of Plakophilin 2 cardiomyopathy

“…Recent efforts have characterized regional patterns in variant–disease association in genes including TTN , MYH7 , DSP , and most recently MYBPC3. 3 – 7 We showed that agnostic regional comparison of variants found in disease-associated cohorts versus the general population confirmed known functional domains and novel areas of interest in the gene RBM20. 8 Here, we refine and apply this heuristic along with a gene-wide analysis to investigate the genetic architecture of a well-known cause of arrhythmogenic cardiomyopathy (ACM): Plakophilin 2 ( PKP2 ).…”

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin ( DSP ) Truncating Variant

“…Another showed enrichment of missense variants in the spectrin repeat domain, which is part of the constitutive NMD competent region. 34 While it seems likely that truncating variants in the NMD-incompetent region escape NMD and have a later onset and less deleterious impact, functional work to date has shown highly variable pattern of protein expression representing both haploinsufficiency and dominant negative effects. 35 Our literature review identified biallelic DSP tv localized more often to the constitutive NMD-incompetent region compared with dominant DSP tv, suggesting that single heterozygous DSP tv are more likely to cause disease when occurring in the NMD-competent regions.…”