title: Whole exome sequencing identifies a causal RBM20 mutation in a large pedigree with familial dilated cardiomyopathy.
abstract: BACKGROUND
  Whole exome sequencing is a powerful technique for Mendelian disease gene discovery. However, variant prioritization remains a challenge. We applied whole exome sequencing to identify the causal variant in a large family with familial dilated cardiomyopathy of unknown pathogenesis.
  
  
  RESULTS
  A large family with autosomal dominant, familial dilated cardiomyopathy was identified. Exome capture and sequencing were performed in 3 remotely related, affected subjects predicted to share <0.1% of their genomes by descent. Shared variants were filtered for rarity, evolutionary conservation, and predicted functional significance, and remaining variants were filtered against 71 locally generated exomes. Variants were also prioritized using the Variant Annotation Analysis and Search Tool. Final candidates were validated by Sanger sequencing and tested for segregation. There were 664 shared heterozygous nonsense, missense, or splice site variants, of which 26 were rare (minor allele frequency ≤0.001 or not reported) in 2 public databases. Filtering against internal exomes reduced the number of candidates to 2, and of these, a single variant (c.1907 G>A) in RBM20, segregated with disease status and was absent in unaffected internal reference exomes. Bioinformatic prioritization with Variant Annotation Analysis and Search Tool supported this result.
  
  
  CONCLUSIONS
  Whole exome sequencing of remotely related dilated cardiomyopathy subjects from a large, multiplex family, followed by systematic filtering, identified a causal RBM20 mutation without the need for linkage analysis.
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Quinn S
authors.initials: QS
authors.lastname: Wells
authors.forename: Jason R
authors.initials: JR
authors.lastname: Becker
authors.forename: Yan R
authors.initials: YR
authors.lastname: Su
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mosley
authors.forename: Peter
authors.initials: P
authors.lastname: Weeke
authors.forename: Laura
authors.initials: L
authors.lastname: D'Aoust
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Ausborn
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Ramirez
authors.forename: Jean P
authors.initials: JP
authors.lastname: Pfotenhauer
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Naftilan
authors.forename: Larry
authors.initials: L
authors.lastname: Markham
authors.forename: Vernat
authors.initials: V
authors.lastname: Exil
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019295:Computational Biology; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D016601:RNA-Binding Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D016601:RNA-Binding Proteins; C543725:ribonucleic acid binding motif protein 20, human
keywords: exome; genetic heart disease; heart failure