Guangzhou Institute of Forensic Science, Guangzhou 510030, China.
Departments of Medicine, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States.
Forensic Sci Int. 2014 Mar;236:38-45. doi: 10.1016/j.forsciint.2013.12.033. Epub 2014 Jan 7.
Sudden unexplained nocturnal death syndrome (SUNDS) remains an enigma to both forensic pathologists and physicians. Previous epidemiological, clinical, and pilot genetic studies have implicated that SUNDS is most likely a disease allelic to Brugada syndrome (BrS). We have performed postmortem genetic testing to address the spectrum and role of genetic abnormalities in the SCN5A-encoded cardiac sodium channel and its several associated proteins in SUNDS victims from Southern China. Genomic DNA extracted from the blood samples of 123 medico-legal autopsy-negative SUNDS cases and 104 sex-, age- and ethnic-matched controls from Southern China underwent comprehensive amino acid coding region mutational analysis for the BrS associated genes SCN5A, SCN1B, SCN2B, SCN3B, SCN4B, MOG1, and GPD1-L using PCR and direct sequencing. We identified a total of 7 unique (4 novel) putative pathogenic mutations (all in SCN5A; V95I, R121Q [2 cases], R367H, R513H, D870H, V1764D, and S1937F) in 8/123 (6.5%) SUNDS cases. Three SCN5A mutations (V95I, R121Q, and R367H) have been previously implicated in BrS. An additional 8 cases hosted rare variants of uncertain clinical significance (SCN5A: V1098L, V1202M, R1512W; SCN1B: V138I [3 cases], T189M [2 cases]; SCN3B: A195T). There were no non-synonymous mutations found in SCN2B, SCN4B, MOG1, or GPD1-L. This first comprehensive genotyping for SCN5A and related genes in the Chinese Han population with SUNDS discovered 13 mutations, 4 of them novel, in 16 cases, which suggests cardiac sodium channel dysfunction might account for the pathogenesis of 7-13% of SUNDS in Southern China.
突发性不明原因夜间死亡综合征（SUNDS）仍然是法医病理学家和医生的一个谜。先前的流行病学、临床和试点遗传研究表明，SUNDS 很可能是 Brugada 综合征（BrS）的等位基因疾病。我们已经进行了尸检后的基因检测，以解决在中国南方的 SUNDS 受害者中 SCN5A 编码的心脏钠离子通道及其几种相关蛋白的遗传异常的范围和作用。从中国南方的 123 例法医学尸检阴性的 SUNDS 病例和 104 名性别、年龄和种族匹配的对照者的血液样本中提取基因组 DNA，对与 BrS 相关的基因 SCN5A、SCN1B、SCN2B、SCN3B、SCN4B、MOG1 和 GPD1-L 进行了全面的氨基酸编码区突变分析，使用 PCR 和直接测序。我们总共在 8/123（6.5%）的 SUNDS 病例中发现了 7 个独特的（4 个新的）假定致病性突变（均在 SCN5A 中；V95I、R121Q[2 例]、R367H、R513H、D870H、V1764D 和 S1937F）。3 个 SCN5A 突变（V95I、R121Q 和 R367H）以前与 BrS 有关。另外 8 个病例携带不确定临床意义的罕见变异（SCN5A：V1098L、V1202M、R1512W；SCN1B：V138I[3 例]、T189M[2 例]；SCN3B：A195T）。在 SCN2B、SCN4B、MOG1 或 GPD1-L 中没有发现非同义突变。这是在中国汉族人群中对 SUNDS 进行的第一个 SCN5A 和相关基因的全面基因分型，在 16 例中发现了 13 个突变，其中 4 个是新的，这表明心脏钠离子通道功能障碍可能导致中国南方 7-13%的 SUNDS 的发病机制。
