title: Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred.
abstract: BACKGROUND
  Hereditary pancreatitis is the early onset form of chronic pancreatitis that is carried in an autosomal dominant pattern with variable penetrance. While 80% of hereditary pancreatitis has been shown to be due to a single mutation in the trypsinogen gene PRSS1, a number of hereditary pancreatitis families have no identified genetic cause for illness; thus no reliable screening options or clear therapy.
  
  
  OBJECTIVE
  To explore the use of massive parallel DNA sequencing technology to discover the etiology of pancreatitis in a family with idiopathic hereditary pancreatitis.
  
  
  METHODS
  Candidate gene screening and verification within a kindred.
  
  
  METHODS
  Prospective cohort study, university based.
  
  
  METHODS
  Kindred with idiopathic hereditary pancreatitis.
  
  
  METHODS
  None.
  
  
  METHODS
  Identification of DNA variants predicted to increase susceptibility to pancreatitis.
  
  
  METHODS
  Whole exome sequencing of two distantly related subjects with variant-specific confirmation in the subjects and other family members.
  
  
  RESULTS
  We identified three deleterious genetic changes in the three major pancreatitis associated genes (PRSS1 CNV, SPINK1 c.27delC and CFTR R117H), two of which were carried by each patient. Individual targeted assays confirmed these variations in the two whole exome sequencing patients as well as affected and non-affected pedigree members.
  
  
  CONCLUSIONS
  Whole exome sequencing was useful for rapid screening of candidate genes linked to pancreatitis. This method opens the door for time- and cost-effective screening of multiple disease-associated genes and modifying factors that associate in different ways to generate a complex genetic disorder.
authors.affiliation: Department of Medicine, University of Pittsburgh. Pittsburgh, PA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: LaRusch
authors.forename: M Michael
authors.initials: MM
authors.lastname: Barmada
authors.forename: Shiela
authors.initials: S
authors.lastname: Solomon
authors.forename: David C
authors.initials: DC
authors.lastname: Whitcomb
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D010195:Pancreatitis / Q000235:genetics*; D010375:Pedigree; D011446:Prospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods*; D014357:Trypsin / Q000235:genetics; D014359:Trypsin Inhibitor, Kazal Pancreatic
chemical_list: C505032:CFTR protein, human; D002352:Carrier Proteins; C486642:SPINK1 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014359:Trypsin Inhibitor, Kazal Pancreatic; C489303:PRSS1 protein, human; D014357:Trypsin