title: Is sudden unexplained nocturnal death syndrome in Southern China a cardiac sodium channel dysfunction disorder?
abstract: 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.
authors: Guangzhou Institute of Forensic Science, Guangzhou 510030, China.
authors: Chao
authors: C
authors: Liu
authors: Departments of Medicine, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States.
authors: David J
authors: DJ
authors: Tester
authors: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors: Yiding
authors: Y
authors: Hou
authors: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors: Wen
authors: W
authors: Wang
authors: Guangzhou Institute of Forensic Science, Guangzhou 510030, China.
authors: Guoli
authors: G
authors: Lv
authors: Departments of Medicine, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States.
authors: Michael J
authors: MJ
authors: Ackerman
authors: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53792, United States.
authors: Jonathan C
authors: JC
authors: Makielski
authors: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: chengjd@mail.sysu.edu.cn.
authors: Jianding
authors: J
authors: Cheng
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002681:China; D003645:Death, Sudden / Q000209:etiology*; D005006:Ethnicity / Q000235:genetics; D005091:Exons; D053803:Forensic Genetics; D005787:Gene Frequency; D005820:Genetic Testing; D005838:Genotype; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012890:Sleep; D062546:Voltage-Gated Sodium Channel beta Subunits / Q000235:genetics*; D055815:Young Adult; D020931:ran GTP-Binding Protein / Q000235:genetics
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D062546:Voltage-Gated Sodium Channel beta Subunits; C525035:GPD1L protein, human; D005993:Glycerolphosphate Dehydrogenase; C498735:RANGNRF protein, human; D020931:ran GTP-Binding Protein
keywords: Cardiac sodium channel β subunits; GPD1-L gene; MOG1 gene; SCN5A gene; Sudden unexplained nocturnal death syndrome (SUNDS)