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.
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, SPINK1c.27delC and CFTRR117H), 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.
Authors: Alexander Schneider; Jessica Larusch; Xiumei Sun; Amy Aloe; Janette Lamb; Robert Hawes; Peter Cotton; Randall E Brand; Michelle A Anderson; Mary E Money; Peter A Banks; Michele D Lewis; John Baillie; Stuart Sherman; James Disario; Frank R Burton; Timothy B Gardner; Stephen T Amann; Andres Gelrud; Ryan George; Matthew J Rockacy; Sirvart Kassabian; Jeremy Martinson; Adam Slivka; Dhiraj Yadav; Nevin Oruc; M Michael Barmada; Raymond Frizzell; David C Whitcomb Journal: Gastroenterology Date: 2010-10-25 Impact factor: 22.682
Authors: D C Whitcomb; M C Gorry; R A Preston; W Furey; M J Sossenheimer; C D Ulrich; S P Martin; L K Gates; S T Amann; P P Toskes; R Liddle; K McGrath; G Uomo; J C Post; G D Ehrlich Journal: Nat Genet Date: 1996-10 Impact factor: 38.330
Authors: G Talamini; C Bassi; M Falconi; L Frulloni; V Di Francesco; B Vaona; P Bovo; L Rigo; A Castagnini; G Angelini; I Vantini; P Pederzoli; G Cavallini Journal: Pancreas Date: 1996-03 Impact factor: 3.327
Authors: P Felderbauer; W Klein; K Bulut; N Ansorge; G Dekomien; I Werner; J T Epplen; F Schmitz; W E Schmidt Journal: Scand J Gastroenterol Date: 2006-03 Impact factor: 2.423
Authors: Nathan Howes; Markus M Lerch; William Greenhalf; Deborah D Stocken; Ian Ellis; Peter Simon; Kaspar Truninger; Rudi Ammann; Giorgio Cavallini; Richard M Charnley; Generoso Uomo; Miriam Delhaye; Julius Spicak; Brendan Drumm; Jan Jansen; Roger Mountford; David C Whitcomb; John P Neoptolemos Journal: Clin Gastroenterol Hepatol Date: 2004-03 Impact factor: 11.382
Authors: C Le Maréchal; J M Chen; C Le Gall; G Plessis; J Chipponi; N A Chuzhanova; O Raguénès; C Férec Journal: Hum Mutat Date: 2004-02 Impact factor: 4.878
Authors: David N Cooper; Michael Krawczak; Constantin Polychronakos; Chris Tyler-Smith; Hildegard Kehrer-Sawatzki Journal: Hum Genet Date: 2013-07-03 Impact factor: 4.132