title: Whole-exome sequencing of a pedigree segregating asthma.
abstract: BACKGROUND
  Despite the success of genome-wide association studies for asthma, few, if any, definitively causal variants have been identified and there is still a substantial portion of the heritability of the disease yet to be discovered. Some of this "missing heritability" may be accounted for by family-specific coding variants found to be segregating with asthma.
  
  
  METHODS
  To identify family-specific variants segregating with asthma, we recruited one family from a previous study of asthma as reporting multiple asthmatic and non-asthmatic children. We performed whole-exome sequencing on all four children and both parents and identified coding variants segregating with asthma that were not found in other variant databases.
  
  
  RESULTS
  Ten novel variants were identified that were found in the two affected offspring and affected mother, but absent in the unaffected father and two unaffected offspring. Of these ten, variants in three genes (PDE4DIP, CBLB, and KALRN) were deemed of particular interest based on their functional prediction scores and previously reported function or asthma association. We did not identify any common risk variants segregating with asthma, however, we did observe an increase in the number of novel, nonsynonymous variants in asthma candidate genes in the asthmatic children compared to the non-asthmatic children.
  
  
  CONCLUSIONS
  This is the first report applying exome sequencing to identify asthma susceptibility variants. Despite having sequenced only one family segregating asthma, we have identified several potentially functional variants in interesting asthma candidate genes. This will provide the basis for future work in which more families will be sequenced to identify variants across families that cluster within genes.
authors.affiliation: Department of Chronic Disease Epidemiology, Yale School of Public Health, 60 College St, New Haven, CT 06520, USA. andrew.dewan@yale.edu
authors.forename: Andrew T
authors.initials: AT
authors.lastname: DeWan
authors.forename: Kathryn Brigham
authors.initials: KB
authors.lastname: Egan
authors.forename: Karen
authors.initials: K
authors.lastname: Hellenbrand
authors.forename: Keli
authors.initials: K
authors.lastname: Sorrentino
authors.forename: Nicole
authors.initials: N
authors.lastname: Pizzoferrato
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bracken
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001249:Asthma / Q000235:genetics*; D002648:Child; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult