Table2_Long QTc in hypertrophic cardiomyopathy: A consequence of structural myocardial damage or a distinct genetic disease?.docx

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, characterized by the presence of unexplained left ventricular hypertrophy. This condition is often associated with electrocardiographic abnormalities including QTc prolongation occurring in 13% of patients. The main explanation for prolonged QTc in HCM is myocardial hypertrophy and the related structural damage. However, other mechanisms, including long QT syndrome (LQTS) genes mutations, may be involved. In the present study we explored the hypothesis of a distinct genetic basis underlying QTc prolongation in HCM by investigating the potential co-inheritance of pathogenic gene variants associated with LQTS and HCM. For this purpose, starting from a cohort of 150 HCM patients carrying pathogenic variants in sarcomere genes, we selected 25 patients carrying a QTc prolongation unexplained by any other cause. The QTc was considered prolonged if greater than 450 ms in males and greater than 470 ms in females. The NGS analysis was performed with Illumina TrueSight Cardio panel genes on Illumina MiniSeq platform. We identified pathogenic/likely pathogenic variants in the KCNQ1 in two patients (c.1781G > A, p. Arg594Gln; c.532G > A, p. Ala178Thr) (8%). Variants of uncertain significance were identified in SCN5A, KCNJ5, AKAP9 and ANK2 in four patients (16%). Although the results are limited by the small number of patients included in the study, they highlight a minor contribution of LQTS genes for QTc prolongation in HCM patients. The screening for ion channel genes mutations may be considered in HCM patients with prolonged QTc unexplained by any other cause. This in-depth molecular diagnosis may contribute to improve risk stratification and treatment planning.

肥厚型心肌病（Hypertrophic cardiomyopathy, HCM）是一种常染色体显性遗传病，以不明原因的左心室肥厚为核心特征。该疾病常合并心电图异常，其中13%的患者可出现校正QT间期（QTc）延长。HCM患者出现QTc延长的主要机制为心肌肥厚及其相关结构损伤，但也可能存在其他致病途径，例如长QT综合征（Long QT Syndrome, LQTS）相关基因突变。
本研究旨在验证“HCM患者的QTc延长存在独特遗传基础”这一假说，通过探究与LQTS及HCM相关的致病性基因变异的共遗传风险开展相关分析。为此，我们从150例携带肌节基因致病性变异的HCM患者队列中，筛选出25例存在不明原因QTc延长的受试者。本研究判定QTc延长的标准为：男性QTc＞450ms，女性QTc＞470ms。
实验检测采用Illumina MiniSeq测序平台，搭配Illumina TruSight心血管靶向测序panel完成下一代测序（Next-Generation Sequencing, NGS）分析。结果显示，2例患者（占比8%）携带KCNQ1基因的致病性/可能致病性变异：c.1781G>A（p.Arg594Gln）与c.532G>A（p.Ala178Thr）。另有4例患者（占比16%）在SCN5A、KCNJ5、AKAP9及ANK2基因中检出意义未明的变异。
尽管本研究纳入的患者样本量较小，结果存在一定局限性，但研究结果提示，LQTS相关基因在HCM患者QTc延长的发生过程中仅发挥次要作用。对于存在不明原因QTc延长的HCM患者，可考虑开展离子通道基因变异筛查。此类深入的分子诊断有助于优化患者的风险分层与治疗方案制定。