Table1_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（HCM）是一种常染色体显性遗传疾病，其特征为左心室肥厚原因不明。该病常伴有心电图异常，包括13%的患者出现的QTc延长。HCM中QTc延长的主要原因被认为是心肌肥厚及其相关的结构损伤。然而，其他机制，包括长QT综合征（LQTS）基因突变，也可能参与其中。在本研究中，我们通过调查与LQTS和HCM相关的致病基因变体可能的共遗传，来探究HCM中QTc延长的独特遗传基础的假设。为此，我们从携带肌节基因致病变异的150例HCM患者队列中选取了25例QTc延长且无法由其他原因解释的患者。在男性中，如果QTc大于450毫秒，在女性中，如果QTc大于470毫秒，则被视为延长。NGS分析是在Illumina MiniSeq平台上使用Illumina TrueSight Cardio基因面板进行的。我们在两名患者中（c.1781G>A，p. Arg594Gln；c.532G>A，p. Ala178Thr）（8%）中鉴定出致病/可能致病的变异。在四名患者中（16%）鉴定出意义未明的变异，涉及SCN5A、KCNJ5、AKAP9和ANK2。尽管研究结果受限于研究中纳入的患者数量较少，但它们突显了LQTS基因对HCM患者QTc延长的轻微贡献。对于任何其他原因无法解释的QTc延长HCM患者，考虑筛查离子通道基因突变可能是一个选择。这种深入的分子诊断可能有助于改善风险分层和治疗规划。