Background:Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM.Methods:A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed.Results:Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%).Conclusions:In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

中文翻译：

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钙粘蛋白 2 相关性心律失常性心肌病

背景：致心律失常性心肌病（ACM）是一种遗传性心脏病，其特征是左右心室的纤维脂肪替代，常导致心室功能障碍和危及生命的心律失常。桥粒基因的变异占病例的 60%。我们的目标是确定源自非桥粒钙粘蛋白 2 (CDH2) 致病变异的 ACM 的患病率和临床特征，CDH2 是 ACM 的一种新遗传底物。导致主要 ACM 基因中的变异被组装。CDH2 的基因筛选是通过下一代或 Sanger 测序进行的。只要有可能，在CDH2家族中启动级联筛选- 阳性先证者，并进行临床评估。结果：CDH2 的基因筛查导致鉴定出 7 个罕见变异：在 6 个先证者中鉴定出的 5 个被归类为致病性或可能致病性。在另外 2 名先证者中检测到先前建立的 p.D407N 致病性变异。具有 CDH2 致病性/可能致病性变异的先证者和家庭成员进行了临床评估，并与先前发表的病例一起，共同有助于识别基因特异性特征（该队列中的 13 例和先前发表的 11 例，总共 9 例先证者）和 15 个家庭成员）。大多数CDH2发生室性心律失常事件-阳性受试者（20/24, 83%），而心力衰竭的发生很少（2/24, 8.3%）。在先证者中，持续性室性心动过速和心源性猝死的发生率为 5/9 (56%)。 结论：在这个先前基因型阴性 ACM 患者的全球队列中，具有CDH2致病性/可能致病性变异的先证者的患病率为 1.2% (6 /500）。我们的数据显示，这组CDH2- ACM 患者的室性心律失常发生率很高，而心力衰竭的演变却很少见。