PDF(Pubmed)
Abstract：
Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease at risk of sudden death. Genetic testing impacts greatly in ACM diagnosis, but gene-disease associations have yet to be determined for the increasing number of genes included in clinical panels. Genetic variants evaluation was undertaken for the most relevant non-desmosomal disease genes. We retrospectively studied 320 unrelated Italian ACM patients, including 243 cases with predominant right-ventricular (ARVC) and 77 cases with predominant left-ventricular (ALVC) involvement, who did not carry pathogenic/likely pathogenic (P/LP) variants in desmosome-coding genes. The aim was to assess rare genetic variants in transmembrane protein 43 (TMEM43), desmin (DES), phospholamban (PLN), filamin c (FLNC), cadherin 2 (CDH2), and tight junction protein 1 (TJP1), based on current adjudication guidelines and reappraisal on reported literature data. Thirty-five rare genetic variants, including 23 (64%) P/LP, were identified in 39 patients (16/243 ARVC; 23/77 ALVC): 22 FLNC, 9 DES, 2 TMEM43, and 2 CDH2. No P/LP variants were found in PLN and TJP1 genes. Gene-based burden analysis, including P/LP variants reported in literature, showed significant enrichment for TMEM43 (3.79-fold), DES (10.31-fold), PLN (117.8-fold) and FLNC (107-fold). A non-desmosomal rare genetic variant is found in a minority of ARVC patients but in about one third of ALVC patients; as such, clinical decision-making should be driven by genes with robust evidence. More than two thirds of non-desmosomal P/LP variants occur in FLNC.
摘要：
心律失常性心肌病(ACM)是一种有猝死风险的遗传性心肌病。基因检测对ACM诊断影响很大，但是对于临床小组中越来越多的基因，基因-疾病关联尚未确定。对最相关的非桥粒疾病基因进行遗传变异评估。我们回顾性研究了320名无关的意大利ACM患者，其中主要累及右心室（ARVC）243例，主要累及左心室（ALVC）77例，在桥粒编码基因中不携带致病性/可能致病性（P/LP）变异。目的是评估跨膜蛋白43（TMEM43）中的罕见遗传变异，desmin(DES),磷脂（PLN），丝状蛋白c(FLNC)，钙粘蛋白2（CDH2），和紧密连接蛋白1（TJP1），基于当前的裁决指南和对报告的文献数据的重新评估。35种罕见的遗传变异,包括23（64%）P/LP，在39例患者（16/243ARVC；23/77ALVC）中发现：22FLNC，9DES,2TMEM43，和2CDH2。在PLN和TJP1基因中未发现P/LP变体。基于基因的负担分析，包括文献中报道的P/LP变体，显示TMEM43的显着富集（3.79倍），DES（10.31倍），PLN（117.8倍）和FLNC（107倍）。在少数ARVC患者中发现非桥粒罕见遗传变异，但在约三分之一的ALVC患者中发现；因此，临床决策应由具有可靠证据的基因驱动.超过三分之二的非桥粒P/LP变体发生在FLNC中。
