Department of Obstetrics and Gynecology, and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea.
Heart Rhythm. 2012 Jul;9(7):1090-6. doi: 10.1016/j.hrthm.2012.02.023. Epub 2012 Feb 24.
Heterozygous SCN5A mutations have been associated with varied arrhythmia phenotypes; phenotype severity may range from asymptomatic electrocardiographic changes (mild phenotype) to symptomatic arrhythmias resulting in syncope, cardiac arrest, and sudden cardiac death (severe phenotype) even among family members carrying the same mutation. Risk-stratification schemes for SCN5A mutation carriers remain uncertain.
To determine the role of SCN5A promoter variants and DNA methylation by using a family-based approach in predicting phenotype severity in a kindred with loss-of-function SCN5A mutation.
In a large kindred with a heterozygous SCN5A loss-of-function mutation (1936delC, Q646RfsX5; 22 mutation carriers), we sought SCN5A promoter variants. In addition, we assessed SCN5A and genome-wide DNA methylation profiles on genomic DNA derived from blood (Illumina Human Methylation27 BeadChip).
During systematic survey of the 2.8-kb SCN5A promoter region, we identified 2 single nucleotide polymorphisms in complete linkage disequilibrium (rs41310749 and rs41310239). These promoter variants were significantly associated with disease severity (mild vs severe phenotype) (P = .0007), as all 3 patients with severe phenotype carried the 2-SNP variant on both mutant and wild-type alleles. Analysis did not support a role for the methylation of SCN5A-related genes.
These family-based genetic findings suggest that the presence of specific promoter variants increase the risk of a severe phenotype in heterozygous carriers of an SCN5A loss-of-function mutation.
杂合性 SCN5A 突变与多种心律失常表型相关；表型严重程度可从无症状心电图改变（轻度表型）到导致晕厥、心脏骤停和心源性猝死的有症状心律失常（重度表型）不等，即使在携带相同突变的家庭成员中也是如此。SCN5A 突变携带者的风险分层方案仍不确定。
使用基于家系的方法，确定 SCN5A 启动子变异体和 DNA 甲基化在预测携带失活功能 SCN5A 突变的家系中表型严重程度的作用。
在一个携带有杂合性 SCN5A 失活功能突变（1936delC，Q646RfsX5；22 个突变携带者）的大型家系中，我们寻找 SCN5A 启动子变异体。此外，我们评估了来自血液的 SCN5A 和全基因组 DNA 甲基化谱（Illumina Human Methylation27 BeadChip）。
在对 2.8kb SCN5A 启动子区域进行系统调查时，我们发现了 2 个完全连锁不平衡的单核苷酸多态性（rs41310749 和 rs41310239）。这些启动子变异体与疾病严重程度（轻度与重度表型）显著相关（P=0.0007），因为所有 3 名重度表型患者的突变和野生型等位基因上均携带 2-SNP 变异体。分析不支持 SCN5A 相关基因甲基化的作用。
这些基于家系的遗传发现表明，特定启动子变异体的存在增加了携带 SCN5A 失活突变的杂合子携带者出现重度表型的风险。
