Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred.

CONTEXT 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. DESIGN Candidate gene screening and verification within a kindred. SETTING Prospective cohort study, university based. PATIENTS OR PARTICIPANTS Kindred with idiopathic hereditary pancreatitis. INTERVENTIONS None. MAIN OUTCOME MEASURES 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. CONCLUSION 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.