title: Whole exome sequencing for familial bicuspid aortic valve identifies putative variants.
abstract: BACKGROUND
  Bicuspid aortic valve (BAV) is the most common congenital cardiovascular malformation. Although highly heritable, few causal variants have been identified. The purpose of this study was to identify genetic variants underlying BAV by whole exome sequencing a multiplex BAV kindred.
  
  
  RESULTS
  Whole exome sequencing was performed on 17 individuals from a single family (BAV=3; other cardiovascular malformation, 3). Postvariant calling error control metrics were established after examining the relationship between Mendelian inheritance error rate and coverage, quality score, and call rate. To determine the most effective approach to identifying susceptibility variants from among 54 674 variants passing error control metrics, we evaluated 3 variant selection strategies frequently used in whole exome sequencing studies plus extended family linkage. No putative rare, high-effect variants were identified in all affected but no unaffected individuals. Eight high-effect variants were identified by ≥2 of the commonly used selection strategies; however, these were either common in the general population (>10%) or present in the majority of the unaffected family members. However, using extended family linkage, 3 synonymous variants were identified; all 3 variants were identified by at least one other strategy.
  
  
  CONCLUSIONS
  These results suggest that traditional whole exome sequencing approaches, which assume causal variants alter coding sense, may be insufficient for BAV and other complex traits. Identification of disease-associated variants is facilitated by the use of segregation within families.
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (L.J.M., V.P., K.M.K., L.C.K., M.K., P.D., M.T.W.); Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati OH (L.J.M., K.M.K., M.K., M.T.W.); Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus (L.C.); Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); and Department of Pediatrics, Medical College of Wisconsin, Milwaukee (D.W.B.). lisa.martin@cchmc.org DBenson@chw.org.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (L.J.M., V.P., K.M.K., L.C.K., M.K., P.D., M.T.W.); Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati OH (L.J.M., K.M.K., M.K., M.T.W.); Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus (L.C.); Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); and Department of Pediatrics, Medical College of Wisconsin, Milwaukee (D.W.B.).
authors.forename: Valentina
authors.initials: V
authors.lastname: Pilipenko
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (L.J.M., V.P., K.M.K., L.C.K., M.K., P.D., M.T.W.); Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati OH (L.J.M., K.M.K., M.K., M.T.W.); Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus (L.C.); Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); and Department of Pediatrics, Medical College of Wisconsin, Milwaukee (D.W.B.).
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (L.J.M., V.P., K.M.K., L.C.K., M.K., P.D., M.T.W.); Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati OH (L.J.M., K.M.K., M.K., M.T.W.); Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus (L.C.); Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); and Department of Pediatrics, Medical College of Wisconsin, Milwaukee (D.W.B.).
authors.forename: Linda
authors.initials: L
authors.lastname: Cripe
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (L.J.M., V.P., K.M.K., L.C.K., M.K., P.D., M.T.W.); Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati OH (L.J.M., K.M.K., M.K., M.T.W.); Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus (L.C.); Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); and Department of Pediatrics, Medical College of Wisconsin, Milwaukee (D.W.B.).
authors.forename: Leah C
authors.initials: LC
authors.lastname: Kottyan
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (L.J.M., V.P., K.M.K., L.C.K., M.K., P.D., M.T.W.); Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati OH (L.J.M., K.M.K., M.K., M.T.W.); Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus (L.C.); Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); and Department of Pediatrics, Medical College of Wisconsin, Milwaukee (D.W.B.).
authors.forename: Mehdi
authors.initials: M
authors.lastname: Keddache
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (L.J.M., V.P., K.M.K., L.C.K., M.K., P.D., M.T.W.); Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati OH (L.J.M., K.M.K., M.K., M.T.W.); Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus (L.C.); Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); and Department of Pediatrics, Medical College of Wisconsin, Milwaukee (D.W.B.).
authors.forename: Phillip
authors.initials: P
authors.lastname: Dexheimer
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (L.J.M., V.P., K.M.K., L.C.K., M.K., P.D., M.T.W.); Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati OH (L.J.M., K.M.K., M.K., M.T.W.); Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus (L.C.); Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); and Department of Pediatrics, Medical College of Wisconsin, Milwaukee (D.W.B.).
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Weirauch
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (L.J.M., V.P., K.M.K., L.C.K., M.K., P.D., M.T.W.); Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati OH (L.J.M., K.M.K., M.K., M.T.W.); Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus (L.C.); Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); and Department of Pediatrics, Medical College of Wisconsin, Milwaukee (D.W.B.). lisa.martin@cchmc.org DBenson@chw.org.
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
mesh_terms: D000328:Adult; D001021:Aortic Valve / Q000002:abnormalities* / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D019295:Computational Biology / Q000379:methods; D059472:Exome; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006349:Heart Valve Diseases / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D010641:Phenotype; D015203:Reproducibility of Results
keywords: bicuspid aortic valve; exome; quality control