Isaacs Aaron, Barysenka Andrei, Ter Bekke Rachel M A, Helderman-van den Enden Apollonia T J M, van den Wijngaard Arthur, Volders Paul G A, Stoll Monika
Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands; Department of Physiology, Maastricht University, Maastricht, the Netherlands.
Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
Heart Rhythm. 2023 May;20(5):720-727. doi: 10.1016/j.hrthm.2023.02.004. Epub 2023 Feb 9.
The Worm Study, ascertained from a multigeneration pedigree segregating a single amino acid deletion in SCN5A (c.4850_4852delTCT, p.(Phe1617del), rs749697698), is characterized by substantial phenotypic heterogeneity and overlap of sudden cardiac death, long-QT syndrome, cardiac conduction disease, Brugada syndrome, and isorhythmic atrioventricular dissociation. Linkage analysis for a synthetic trait derived from these phenotypes identified a single peak (logarithm of the odds [LOD] = 4.52) at the SCN5A/SCN10A/SCN11A locus on chromosome 3.
This study explored the role of additional genetic variation in the chromosome 3 locus as a source of phenotypic heterogeneity in the Worm Study population.
Genotypes underlying the linkage peak (n = 70) were characterized using microarrays. Haplotypes were determined using family-aware phasing and a population-specific reference panel. Variants with minor allele frequencies >0.10 were tested for association with cardiac conduction disease and isorhythmic dissociation using LAMP and logistic regression.
Only 1 haplotype carried the p.Phe1617del/rs749697698 deletion, suggesting relatively recent development (∼18 generations); this haplotype contained 5 other missense variants spanning SCN5A/SCN10A/SCN11A. Noncarrier haplotypes (n = 74) ranged in frequency from 0.5% to 5%. Although no variants were associated with cardiac conduction disease, a homozygous missense variant in SCN10A was associated with isorhythmic dissociation after correction for multiple comparisons (odds ratio 11.23; 95% confidence interval 2.76-23.39; P = 1.2 × 10). This variant (rs12632942) was previously associated with PR interval.
Our data suggest that other variants, alongside a pathogenic mutation, are associated with phenotypic heterogeneity. Single-mutation screening may be insufficient to predict electrical heart disease in patients and family members. In the Worm Study population, segregating a pathogenic SCN5A mutation, compound variation in the SCN5A/SCN10A/SCN11A locus determines arrhythmic outcome.
蠕虫研究是从一个多代家系中确定的，该家系中SCN5A存在一个单氨基酸缺失（c.4850_4852delTCT，p.(Phe1617del)，rs749697698），其特征是具有显著的表型异质性，且心脏性猝死、长QT综合征、心脏传导疾病、Brugada综合征和等节律性房室分离存在重叠。对源自这些表型的综合性状进行连锁分析，在3号染色体的SCN5A/SCN10A/SCN11A位点发现了一个单一峰值（优势对数[LOD]=4.52）。
本研究探讨3号染色体位点上其他遗传变异作为蠕虫研究人群表型异质性来源的作用。
使用微阵列对连锁峰值下的基因型（n = 70）进行特征分析。使用家族感知分相和特定人群参考面板确定单倍型。对次要等位基因频率>0.10的变异进行检测，以使用LAMP和逻辑回归分析其与心脏传导疾病和等节律分离的相关性。
只有1个单倍型携带p.Phe1617del/rs749697698缺失，表明其相对较新出现（约18代）；该单倍型包含跨越SCN5A/SCN10A/SCN11A的5个其他错义变异。非携带者单倍型（n = 74）的频率范围为0.5%至5%。虽然没有变异与心脏传导疾病相关，但在进行多重比较校正后，SCN10A中的一个纯合错义变异与等节律分离相关（优势比11.23；95%置信区间2.76 - 23.39；P = 1.2×10）。该变异（rs12632942）先前与PR间期相关。
我们的数据表明，除了致病突变外，其他变异也与表型异质性相关联。单突变筛查可能不足以预测患者及其家庭成员的心脏电疾病。在蠕虫研究人群中，存在致病性SCN5A突变，SCN5A/SCN10A/SCN11A位点的复合变异决定心律失常结局。
