Department of Cardiology, Section 2142, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
J Med Genet. 2010 Nov;47(11):736-44. doi: 10.1136/jmg.2010.077891. Epub 2010 Sep 23.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a lethal condition characterised by ventricular tachyarrhythmias, right and/or left ventricular involvement and fibrofatty infiltrations in the myocardium. The disease has been associated with mutations in genes encoding desmosomal proteins.
To thoroughly evaluate an ARVC cohort for desmosomal mutations and large genomic rearrangements and characterise the phenotype associated with double-mutation carrier status.
65 unrelated patients (55 fulfilling current criteria and 10 borderline cases) were screened for mutations in all known desmosome genes (desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP) and plakophilin-2 (PKP2)) and TGFb3. Presence of genomic rearrangements was assessed by multiplex ligation-dependent probe amplification. Results The screening identified 19 different mutations: two mutations in DSG2, four in DSC2, two in DSP (one heterozygous and one homozygous), four in JUP (one patient with compound heterozygous) and seven in PKP2. No genomic rearrangements or mutations in TGFb3 were identified. Ten of the mutations were novel. Seven families carried more than one mutation. Clinical evaluation of these families showed a variable phenotype associated with the double-mutation carrier status. The homozygous desmoplakin mutation (DSP p.G2056R+p.G2056R) carrier came from a consanguineous Danish family and had left ventricular involvement, palmar keratoderma and curly hair consistent with a Carvajal-like syndrome.
33% of patients in this Danish cohort with ARVC carried desmosomal mutations with a surprisingly wide mutation spectrum. A substantial proportion of patients carried more than one mutation. Our study supports comprehensive desmosomal mutation screening beyond the first encountered mutation, whereas routine screening for genomic rearrangements does not seem indicated.
致心律失常性右室心肌病（ARVC）是一种致命性疾病，其特征为室性心动过速、右心室和/或左心室受累以及心肌纤维脂肪浸润。该疾病与桥粒蛋白编码基因的突变有关。
全面评估 ARVC 患者的桥粒突变和大片段基因重排情况，并描述双突变携带者的表型特征。
对 65 例（55 例符合现行标准，10 例为边缘病例）不相关的患者进行所有已知桥粒基因（桥粒胶蛋白-2（DSC2）、桥粒芯糖蛋白-2（DSG2）、桥粒斑蛋白（DSP）、桥粒结合蛋白（JUP）和桥粒斑蛋白-2（PKP2）和 TGFb3 的突变筛查。采用多重连接依赖性探针扩增检测大片段基因重排情况。结果：筛查发现 19 种不同的突变：DSG2 中的两种突变、DSC2 中的四种突变、DSP 中的两种突变（一种为杂合子，一种为纯合子）、JUP 中的四种突变（一种患者为复合杂合子）和 PKP2 中的七种突变。未发现 TGFb3 的基因重排或突变。其中 10 种突变为新发现。7 个家系携带不止一种突变。对这些家系的临床评估显示，双突变携带者具有不同的表型特征。携带纯合子 desmoplakin 突变（DSP p.G2056R+p.G2056R）的患者来自丹麦一个近亲家庭，具有左心室受累、手掌角化过度和卷发，与 Carvajal 样综合征一致。
在丹麦 ARVC 患者队列中，33%的患者携带桥粒突变，具有非常广泛的突变谱。相当一部分患者携带不止一种突变。本研究支持除首次发现的突变外，还应进行全面的桥粒基因突变筛查，而常规筛查大片段基因重排似乎没有必要。
