title: Whole-exome sequencing in familial atrial fibrillation.
abstract: OBJECTIVE
  Positional cloning and candidate gene approaches have shown that atrial fibrillation (AF) is a complex disease with familial aggregation. Here, we employed whole-exome sequencing (WES) in AF kindreds to identify variants associated with familial AF.
  
  
  RESULTS
  WES was performed on 18 individuals in six modestly sized familial AF kindreds. After filtering very rare variants by multiple metrics, we identified 39 very rare and potentially pathogenic variants [minor allele frequency (MAF) ≤0.04%] in genes not previously associated with AF. Despite stringent filtering >1 very rare variants in the 5/6 of the kindreds were identified, whereas no plausible variants contributing to familial AF were found in 1/6 of the kindreds. Two candidate AF variants in the calcium channel subunit genes (CACNB2 and CACNA2D4) were identified in two separate families using expression data and predicted function.
  
  
  CONCLUSIONS
  By coupling family data with exome sequencing, we identified multiple very rare potentially pathogenic variants in five of six families, suggestive of a complex disease mechanism, whereas none were identified in the remaining AF pedigree. This study highlights some important limitations and challenges associated with performing WES in AF including the importance of having large well-curated multi-generational pedigrees, the issue of potential AF misclassification, and limitations of WES technology when applied to a complex disease.
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Weeke
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Raafia
authors.initials: R
authors.lastname: Muhammad
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Delaney
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Shaffer
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mosley
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Blair
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Short
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Stubblefield
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville 37323-6602, TN, USA.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville 37323-6602, TN, USA.
authors.forename: Dawood
authors.initials: D
authors.lastname: Darbar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D012042:Registries; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D022821:RNA Splice Sites
keywords: Atrial fibrillation; Calcium signalling; Exome; Family study; Genetics
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