Department of Cardiovascular Medicine (Clinician-Investigator Training Program), Mayo Clinic, Rochester, MN, USA.
Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Europace. 2020 Apr 1;22(4):622-631. doi: 10.1093/europace/euz337.
To determine the prevalence and in vitro electrophysiological (EP) phenotype of ultra-rare SCN5A variants of uncertain significance (VUS) identified in unexplained sudden cardiac arrest (SCA) survivors.
Retrospective review of 73 unexplained SCA survivors was used to identify all patients that underwent a form of genetic testing that included comprehensive SCN5A analysis. Ultra-rare SCN5A variants (minor allele frequency < 0.005) were adjudicated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Variants designated as VUS were expressed heterologously and characterized using the whole-cell patch clamp technique. Overall, 60/73 (82%; the average age at SCA 28 ± 12 years) unexplained SCA survivors had received SCN5A genetic testing. Of these, 5/60 (8.3%) had an ultra-rare SCN5A variant. All SCN5A variants were classified as VUS. Whereas the single SCN5A VUS (p.Asp872Asn-SCN5A) identified in an unexplained SCA survivor with PR interval prolongation and inferior early repolarization conferred a loss-of-function phenotype (46.2% reduction in peak current density; 16 ms slower recovery from inactivation), the four other SCN5A VUS (p.Glu30Gly-SCN5A, p.Gln245Lys-SCN5A, p.Pro648Leu-SCN5A, and p.Glu1240Gln-SCN5A) identified in unexplained SCA survivors without early repolarization/conduction delay were indistinguishable from wild-type Nav1.5 channels.
In the absence of a phenotype(s) potentially attributable to sodium channel dysfunction, all SCN5A VUS identified in unexplained SCA survivors conferred a wild-type EP phenotype in vitro. As the background rate of SCN5A genetic variation is not trivial, great care must be taken to avoid prioritizing genotype over phenotype when attempting to ascertain the root cause of an individual's SCA.
确定在不明原因心搏骤停（SCA）幸存者中发现的极罕见 SCN5A 意义未明变异（VUS）的流行率和体外电生理（EP）表型。
回顾性分析了 73 例不明原因 SCA 幸存者，以确定所有接受包括全面 SCN5A 分析在内的某种基因检测的患者。根据 2015 年美国医学遗传学与基因组学学会（ACMG）指南，对极罕见 SCN5A 变异（次要等位基因频率<0.005）进行裁决。将被指定为 VUS 的变异进行异源表达，并使用全细胞贴附式膜片钳技术进行特征分析。总体而言，73 例不明原因 SCA 幸存者中有 60 例（平均 SCA 年龄 28±12 岁）接受了 SCN5A 基因检测。其中，5/60（8.3%）有极罕见的 SCN5A 变异。所有 SCN5A 变异均被归类为 VUS。在一名不明原因 SCA 幸存者中发现的单一 SCN5A VUS（p.Asp872Asn-SCN5A），伴有 PR 间期延长和下壁早期复极，表现出失活功能表型（峰电流密度降低 46.2%；失活恢复时间延长 16ms），而在其他四名不明原因 SCA 幸存者中发现的另外四个 SCN5A VUS（p.Glu30Gly-SCN5A、p.Gln245Lys-SCN5A、p.Pro648Leu-SCN5A 和 p.Glu1240Gln-SCN5A）无早期复极/传导延迟，与野生型 Nav1.5 通道无明显区别。
在没有钠通道功能障碍相关表型的情况下，在不明原因 SCA 幸存者中发现的所有 SCN5A VUS 在体外均表现出野生型 EP 表型。由于 SCN5A 遗传变异的背景率并不低，因此在试图确定个体 SCA 的根本原因时，必须非常小心，避免将基因型置于表型之上。
