Chen Peng, Zampawala Zainul, Wang Hong, Wang Luyun
Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiological Disorders, Wuhan, China.
Front Genet. 2024 May 30;15:1409459. doi: 10.3389/fgene.2024.1409459. eCollection 2024.
Long QT syndrome (LQTS) is an inherited malignant arrhythmia syndrome that poses a risk of sudden death. Variants in the Potassium Voltage-Gated Channel Subfamily H Member 2 () gene are known to cause Long QT syndrome through an autosomal dominant inheritance pattern. However, as of now, there have been no reports of any variant leading to Long QT syndrome exhibiting incomplete penetrance that is influenced by gender.
Whole-exome sequencing (WES) was conducted on the proband to identify pathogenic variants. Subsequently, Sanger sequencing was employed to validate the identified likely pathogenic variants in all family members.
We analyzed a pedigree spanning three-generations afflicted by Long QT syndrome. WES revealed a novel missense variant (p.Val630Gly, c.1889 T>G) as the causative factor for the family's phenotype. Within this family, all three male carriers of the variant carriers exhibited the Long QT syndrome phenotype: one experienced sudden death during sleep, another received an implantable cardioverter defibrillator (ICD), and a younger man displayed a prolonged QTc interval without any instances of syncope or malignant arrhythmia to date. Interestingly, the middle-aged female carrier showed no Long QT Syndrome phenotype. However, her offspring, diagnosed with Turner syndrome (45, X) and also a carrier of this variant, experienced frequent syncope starting at 12 years old and was diagnosed with Long QT syndrome, leading to an ICD implantation when she was 15 years old. These observations suggest that the manifestation of Long QT syndrome associated with this KCNH2 variant exhibits incomplete penetrance influenced by gender within this family, indicating potential protective mechanisms against the syndrome in females affected by this variant.
Our investigation has led to the identification of a novel pathogenic variant responsible for Long QT syndrome within a familial context characterized by gender-selective, incomplete penetrance. This discovery highlights a unique pathogenic inheritance pattern for the gene associated with Long QT syndrome, and could potentially shed light on the distinct penetrance behaviors and patterns of the gene. This discovery broadens our exploration of the KCNH2 gene in cardiac arrhythmias, highlighting the intricate genetic dynamics behind Long QT syndrome.
长QT综合征（LQTS）是一种遗传性恶性心律失常综合征，存在猝死风险。已知钾电压门控通道亚家族H成员2（KCNH2）基因的变异通过常染色体显性遗传模式导致长QT综合征。然而，截至目前，尚无任何导致长QT综合征的KCNH2变异表现出受性别影响的不完全外显率的报道。
对先证者进行全外显子组测序（WES）以鉴定致病变异。随后，采用桑格测序法在所有家庭成员中验证鉴定出的可能致病变异。
我们分析了一个三代受累的长QT综合征家系。WES揭示了一种新的KCNH2错义变异（p.Val630Gly，c.1889 T>G）是该家族表型的致病因素。在这个家族中，所有三名KCNH2变异携带者男性均表现出长QT综合征表型：一名在睡眠中猝死，另一名接受了植入式心律转复除颤器（ICD），一名较年轻男性的QTc间期延长，迄今为止未发生任何晕厥或恶性心律失常事件。有趣的是，中年女性携带者未表现出长QT综合征表型。然而，她被诊断为特纳综合征（45,X）且也是该变异携带者的后代，12岁开始频繁晕厥，被诊断为长QT综合征，15岁时接受了ICD植入。这些观察结果表明，与该KCNH2变异相关的长QT综合征的表现在此家族中呈现出受性别影响的不完全外显率，提示该变异影响的女性中存在针对该综合征的潜在保护机制。
我们的研究在一个具有性别选择性、不完全外显率特征的家族背景中鉴定出一种导致长QT综合征的新的致病KCNH2变异。这一发现凸显了与长QT综合征相关的KCNH2基因独特的致病遗传模式，并可能为KCNH2基因不同的外显行为和模式提供线索。这一发现拓宽了我们对KCNH2基因在心律失常方面的探索，突出了长QT综合征背后复杂的遗传动态。
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