Singh Sajya M, Casey Susan A, Berg Allison A, Abdelhadi Raed H, Katsiyiannis William T, Bennett Mosi K, Mackey-Bojack Shannon, Duncanson Emily R, Sengupta Jay D
Research, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota.
Genomic Medicine, Children's Minnesota, Minneapolis, Minnesota.
Am J Med Genet A. 2018 Jul;176(7):1622-1626. doi: 10.1002/ajmg.a.38719.
A novel autosomal-dominant in-frame deletion resulting in a nonsense mutation in the desmoplakin (DSP) gene was identified in association with biventricular arrhythmogenic cardiomyopathy across three generations of a large Caucasian family. Mutations that disrupt the function and structure of desmosomal proteins, including desmoplakin, have been extensively linked to familial arrhythmogenic right ventricular cardiomyopathy (ARVC). Analysis of data from 51 individuals demonstrated the previously undescribed variant p.Cys81Stop (c.243_251delCTTGATGCG) in DSP segregates with a pathogenic phenotype exhibiting variable penetrance and expressivity. The mutation's pathogenicity was first established due to two sudden cardiac deaths (SCDs), each with a biventricular cardiomyopathy identified on autopsy. Of the individuals who underwent genetic screening, 27 of 51 were heterozygous for the DSP mutation (29 total with two obligate carriers). Six of these were subsequently diagnosed with arrhythmogenic cardiomyopathy. An additional nine family members have a conduction disorder and/or myocardial structural changes characteristic of an evolving condition. Previous reports from both human patients and mouse studies proposed DSP mutations with a premature stop codon impart mild to no clinical symptoms. Loss of expression from the abnormal allele via the nonsense-mediated mRNA decay pathway has been implicated to explain these findings. We identified an autosomal-dominant DSP nonsense mutation in a large family that led to SCD and phenotypic expression of arrhythmogenic cardiomyopathy involving both ventricles. This evidence demonstrates the pathogenic significance of this type of desmosomal mutation and provides insight into potential clinical manifestations.
在一个大型白种人家族的三代人中，发现了一种新的常染色体显性框内缺失，该缺失导致桥粒斑蛋白（DSP）基因出现无义突变，与双心室致心律失常性心肌病相关。破坏包括桥粒斑蛋白在内的桥粒蛋白功能和结构的突变，已被广泛认为与家族性致心律失常性右心室心肌病（ARVC）有关。对51名个体的数据进行分析后发现，DSP基因中先前未描述的变体p.Cys81Stop（c.243_251delCTTGATGCG）与一种具有可变外显率和表达度的致病表型共分离。该突变的致病性最初是由于两例心脏性猝死（SCD）而确定的，尸检时均发现有双心室心肌病。在接受基因筛查的个体中，51人中有27人是DSP突变的杂合子（包括两名必然携带者，共29人）。其中6人随后被诊断为致心律失常性心肌病。另外9名家庭成员有传导障碍和/或心肌结构改变，这是病情发展的特征。此前人类患者和小鼠研究的报告提出，带有过早终止密码子的DSP突变只会导致轻微的临床症状或无临床症状。通过无义介导的mRNA降解途径导致异常等位基因表达缺失，被认为可以解释这些发现。我们在一个大型家族中发现了一种常染色体显性DSP无义突变，该突变导致了心脏性猝死以及涉及双心室的致心律失常性心肌病的表型表达。这一证据证明了这种桥粒突变的致病意义，并为潜在的临床表现提供了见解。
