背景:SCN5A变异体与一系列具有明确表型的心电紊乱相关。然而,它们也可能与复杂的表型特征相关,如重叠综合征,或者多功能性,没有系统地描述。此外,SCN5A与扩张型心肌病(DCM)的关系仍存在争议.
目的:我们旨在(1)评估与致病性(P)/可能致病性(LP)SCN5A变异相关的不同表型,以及(2)确定P/LPSCN5A变异携带者多中心队列中多效性的患病率。
方法:使用一组定制基因对13,510个连续的先证者(9960例心肌病)的DNA进行测序。选择携带杂合的单个P/LPSCN5A变体的个体并进行表型分析。
结果:该研究包括在495名患者中发现的170个P/LP变异。其中,119(70%)仅与一个公认的表型相关:91患有Brugada综合征,15患有3型长QT综合征,六个患有进行性心脏传导疾病,四个与多灶性异位Purkinje相关的过早收缩,还有三个病态窦房结综合征.32个变异(19%)与重叠综合征和/或多效性相关。其余19个变异(11%)与非典型或不清楚的表型相关。其中,8例由8例DCM患者携带,具有有争议的致病基因型/表型联系.
结论:大多数P/LPSCN5A变异体在原发性电紊乱患者中发现,主要是Brugada综合征.近20%与重叠综合征或多效性相关,强调需要进行全面的表型评估。SCN5A变体导致DCM的概念极为罕见(8/9960),如果没有疑问。
BACKGROUND: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes, or pleiotropy, which have not been systematically described. Additionally, the involvement of
SCN5A in dilated cardiomyopathies (DCM) remains controversial.
OBJECTIVE: We aimed to (1) evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and (2) determine the prevalence of pleiotropy in a large multicentric cohort of P/LP
SCN5A variant carriers.
METHODS: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced using a custom panel of genes. Individuals carrying a heterozygous single P/LP
SCN5A variant were selected and phenotyped.
RESULTS: The study included 170 P/LP variants found in 495 patients. Among them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, six with progressive cardiac conduction disease, four with multifocal ectopic Purkinje-related premature contraction, and three with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes and/or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Among those, eight were carried by eight patients presenting with DCM with a debatable causative genotype/phenotype link.
CONCLUSIONS: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of
SCN5A variants causing DCM is extremely rare (8/9960), if not questionable.