PDF(Pubmed)
Abstract：
UNASSIGNED: 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 (KCNH2) 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 KCNH2 variant leading to Long QT syndrome exhibiting incomplete penetrance that is influenced by gender.
UNASSIGNED: 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.
UNASSIGNED: We analyzed a pedigree spanning three-generations afflicted by Long QT syndrome. WES revealed a novel KCNH2 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 KCNH2 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.
UNASSIGNED: Our investigation has led to the identification of a novel pathogenic KCNH2 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 KCNH2 gene associated with Long QT syndrome, and could potentially shed light on the distinct penetrance behaviors and patterns of the KCNH2 gene. This discovery broadens our exploration of the KCNH2 gene in cardiac arrhythmias, highlighting the intricate genetic dynamics behind Long QT syndrome.
UNASSIGNED: 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.
UNASSIGNED: We analyzed a pedigree spanning three-generations afflicted by Long QT syndrome. WES revealed a novel KCNH2 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 KCNH2 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.
UNASSIGNED: Our investigation has led to the identification of a novel pathogenic KCNH2 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 KCNH2 gene associated with Long QT syndrome, and could potentially shed light on the distinct penetrance behaviors and patterns of the KCNH2 gene. This discovery broadens our exploration of the KCNH2 gene in cardiac arrhythmias, highlighting the intricate genetic dynamics behind Long QT syndrome.
摘要：
■长QT综合征（LQTS）是一种遗传性恶性心律失常综合征，有猝死的风险。已知钾电压门控通道亚家族H成员2（KCNH2）基因的变异体通过常染色体显性遗传模式引起长QT综合征。然而,截至目前,没有任何KCNH2变异导致长QT综合征的报道,表现出受性别影响的不完全外显率.
■对先证者进行全外显子组测序(WES)以鉴定致病变体。随后，采用Sanger测序来验证所有家族成员中鉴定的可能致病变体。
■我们分析了一个受长QT综合征折磨的三代谱系。WES揭示了一个新的KCNH2错义变体（p。Val630Gly,c.1889T>G)作为家族表型的致病因素。在这个家庭中,KCNH2变异携带者的所有三个男性携带者均表现出长QT综合征表型：一个在睡眠中突然死亡，另一名患者接受了植入式心律转复除颤器(ICD),一名年轻男子的QTc间期延长，迄今为止没有任何晕厥或恶性心律失常。有趣的是,中年女性携带者无长QT综合征表型。然而,她的后代,诊断为特纳综合征（45，X），也是这种变异的携带者，从12岁开始经历频繁的晕厥，并被诊断为长QT综合征，导致ICD植入时，她是15岁。这些观察结果表明，与该KCNH2变异相关的长QT综合征表现出受该家族性别影响的不完全外显率。表明受该变异影响的女性对该综合征的潜在保护机制。
■我们的调查发现了一种新的致病性KCNH2变异体，该变异体可在具有性别选择性的家族背景下引起长QT综合征，不完整的外显率。这一发现突出了与长QT综合征相关的KCNH2基因的独特致病遗传模式，并可能揭示KCNH2基因的不同外显行为和模式。这一发现拓宽了我们对KCNH2基因在心律失常中的探索，突出了长QT综合征背后复杂的遗传动力学。
■对先证者进行全外显子组测序(WES)以鉴定致病变体。随后，采用Sanger测序来验证所有家族成员中鉴定的可能致病变体。
■我们分析了一个受长QT综合征折磨的三代谱系。WES揭示了一个新的KCNH2错义变体（p。Val630Gly,c.1889T>G)作为家族表型的致病因素。在这个家庭中,KCNH2变异携带者的所有三个男性携带者均表现出长QT综合征表型：一个在睡眠中突然死亡，另一名患者接受了植入式心律转复除颤器(ICD),一名年轻男子的QTc间期延长，迄今为止没有任何晕厥或恶性心律失常。有趣的是,中年女性携带者无长QT综合征表型。然而,她的后代,诊断为特纳综合征（45，X），也是这种变异的携带者，从12岁开始经历频繁的晕厥，并被诊断为长QT综合征，导致ICD植入时，她是15岁。这些观察结果表明，与该KCNH2变异相关的长QT综合征表现出受该家族性别影响的不完全外显率。表明受该变异影响的女性对该综合征的潜在保护机制。
■我们的调查发现了一种新的致病性KCNH2变异体，该变异体可在具有性别选择性的家族背景下引起长QT综合征，不完整的外显率。这一发现突出了与长QT综合征相关的KCNH2基因的独特致病遗传模式，并可能揭示KCNH2基因的不同外显行为和模式。这一发现拓宽了我们对KCNH2基因在心律失常中的探索，突出了长QT综合征背后复杂的遗传动力学。
