title: Mutations in genes encoding cardiac ion channels previously associated with sudden infant death syndrome (SIDS) are present with high frequency in new exome data.
abstract: BACKGROUND
  Sudden infant death syndrome (SIDS) is the leading cause of death in the first 6 months after birth in the industrialized world. The genetic contribution to SIDS has been investigated intensively and to date, 14 cardiac channelopathy genes have been associated with SIDS. Newly published data from National Heart, Lung, and Blood Institute Grand Opportunity (NHLBI GO) Exome Sequencing Project (ESP) provided important knowledge on genetic variation in the background population. Our aim was to identify all variants previously associated with SIDS in ESP to improve the discrimination between plausible disease-causing mutations and variants most likely to be false-positive.
  
  
  METHODS
  The PubMed database was searched to identify SIDS-associated channelopathy variants and the prevalence of these in the ESP population (6500 individuals) were obtained. In silico prediction tools were applied to variants present in ESP and 6 SIDS-associated variants (CAV3 p.C72W, p.T78M; KCNH2 p.R148W, and SCN5A p.S216L, p.V1951L, p.F2004L) were genotyped in our own control population.
  
  
  RESULTS
  Nineteen different missense variants previously associated with SIDS were identified in ESP affecting 225 of 6424 alleles. This corresponds to 1:29 individuals in the ESP population being carriers of a SIDS-associated variant. Genotyping of 6 SIDS-associated variants in our own controls revealed frequencies comparable with those found in ESP.
  
  
  CONCLUSIONS
  A very high prevalence of previously SIDS-associated variants was identified in exome data from population studies. Our findings indicate that the suggested disease-causing role of some of these variants is questionable. A cautious interpretation of these variants must be made when found in SIDS victims.
authors: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
authors: Charlotte
authors: C
authors: Andreasen
authors: Lena
authors: L
authors: Refsgaard
authors: Jonas B
authors: JB
authors: Nielsen
authors: Ahmad
authors: A
authors: Sajadieh
authors: Bo G
authors: BG
authors: Winkel
authors: Jacob
authors: J
authors: Tfelt-Hansen
authors: Stig
authors: S
authors: Haunsø
authors: Anders G
authors: AG
authors: Holst
authors: Jesper H
authors: JH
authors: Svendsen
authors: Morten S
authors: MS
authors: Olesen
mesh_terms: D001741:Black or African American / Q000235:genetics; D051244:Caveolin 3 / Q000235:genetics*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D007473:Ion Channels / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D015995:Prevalence; D013398:Sudden Infant Death / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C417736:CAV3 protein, human; D051244:Caveolin 3; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; C000606913:KCNH2 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human