Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
BMC Med Genomics. 2024 May 7;17(1):126. doi: 10.1186/s12920-024-01900-z.
Long QT syndrome (LQTS) is a cardiac channelopathy characterized by impaired myocardial repolarization that predisposes to life-threatening arrhythmias. This study aimed to elucidate the genetic basis of LQTS in an affected Iranian family using whole exome sequencing (WES).
A 37-year-old woman with a personal and family history of sudden cardiac arrest and LQTS was referred for genetic study after losing her teenage daughter due to sudden cardiac death (SCD). WES was performed and variants were filtered and prioritized based on quality, allele frequency, pathogenicity predictions, and conservation scores. Sanger sequencing confirmed segregation in the family.
WES identified a novel heterozygous frameshift variant (NM_000238.4:c.3257_3258insG; pGly1087Trpfs*32) in the KCNH2 encoding the α-subunit of the rapid delayed rectifier potassium channel responsible for cardiac repolarization. This variant, predicted to cause a truncated protein, is located in the C-terminal region of the channel and was classified as likely pathogenic based on ACMG guidelines. The variant was absent in population databases and unaffected family members.
This study reports a novel KCNH2 frameshift variant in an Iranian family with LQTS, expanding the spectrum of disease-causing variants in this gene. Our findings highlight the importance of the C-terminal region in KCNH2 for proper channel function and the utility of WES in identifying rare variants in genetically heterogeneous disorders like LQTS. Functional characterization of this variant is warranted to fully elucidate its pathogenic mechanisms and inform personalized management strategies.
长 QT 综合征（LQTS）是一种以心肌复极障碍为特征的心脏通道病，易发生危及生命的心律失常。本研究旨在通过外显子组测序（WES）阐明一个受影响的伊朗家系中 LQTS 的遗传基础。
一名 37 岁女性，有个人和家族性心搏骤停和 LQTS 病史，在因心搏骤停导致其十几岁的女儿死亡后，因遗传研究而被转介。进行了 WES，并根据质量、等位基因频率、致病性预测和保守分数对变体进行过滤和优先级排序。Sanger 测序在家系中证实了遗传分离。
WES 发现了一种新的杂合移码变异（NM_000238.4：c.3257_3258insG；pGly1087Trpfs*32），位于快速延迟整流钾通道α亚单位的 KCNH2 中，负责心脏复极。该变体预测会导致截短蛋白，位于通道的 C 端区域，根据 ACMG 指南归类为可能致病。该变体在人群数据库和未受影响的家族成员中均不存在。
本研究报告了一个伊朗家系中存在 KCNH2 移码变异，扩展了该基因导致疾病的变异谱。我们的发现强调了 KCNH2 的 C 端区域对于通道功能的重要性，以及 WES 在识别遗传异质性疾病（如 LQTS）中的罕见变异方面的实用性。需要对该变体进行功能特征分析，以充分阐明其致病机制，并为个体化管理策略提供信息。
