Valentina Maria Sofia1, Letizia Da Sacco2, Cecilia Surace3, Anna Cristina Tomaiuolo4, Silvia Genovese3, Simona Grotta5, Maria Gnazzo3, Laura Ciocca3, Stefano Petrocchi3, Federico Alghisi6, Enza Montemitro6, Luigi Martemucci7, Ausilia Elce8, Vincenzina Lucidi6, Giuseppe Castaldo9, Adriano Angioni10. 1. Laboratory of Medical Genetics, "Bambino Gesù" Children's Hospital, IRCCS, Rome. 2. Multifactorial Diseases and Complex Phenotypes Research Area, "Bambino Gesù" Children's Hospital, IRCCS. 3. Laboratory of Medical Genetics, "Bambino Gesù" Children's Hospital, IRCCS. 4. Laboratory of Medical Genetics, "Bambino Gesù" Children's Hospital. 5. Laboratory of Medical Genetics, "Bambino Gesù" Children's Hospital, IRCCS; Present address: S. Pietro Fatebenefratelli Hospital, UOSD Medical Genetics. 6. Cystic Fibrosis Unit, "Bambino Gesù" Children's Hospital, IRCCS. 7. Pediatria Sistematica, A.O. Santobono-Pausilipon. 8. Ceinge-Biotecnologie avanzate, Naples, Università Telematica Pegaso, Naples, Italy. 9. Ceinge-Biotecnologie avanzate, Naples, Dipartimento di Medicina Molecolare and Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy. 10. Laboratory of Medical Genetics, "Bambino Gesù" Children's Hospital, IRCCS, Viale di San Paolo 15, 00146 Rome, Italy, 0668592536.
Abstract
Rationale: Genetic features of Chronic Pancreatitis (CP) have been extensively investigated mainly testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. Objectives: 80 patients with Idiopathic CP were investigated using Next Generation Sequencing approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen; modifier genes of Cystic Fibrosis phenotype; pancreatic secretion and ion homeostasis; Calcium signalling and zymogen granules exocytosis; autophagy; autoimmune pancreatitis related genes. Results: We detected mutations in 34 out of 70 genes examined; 64/80 patients (80.0%) were positive for mutations in one or more genes, 16/80 patients (20.0%) had no mutations. Mutations in CFTR were detected in 32/80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38/64 patients positive for mutations showed variants in two or more genes (59.3%). Conclusions: Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in chronic pancreatitis and that trans-heterozygosity may predispose to the idiopathic CP phenotype.
Rationale: Genetic features of Chronic Pancreatitis (CP) have been extensively investigated mainly testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. Objectives: 80 patients with Idiopathic CP were investigated using Next Generation Sequencing approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen; modifier genes of Cystic Fibrosis phenotype; pancreatic secretion and ion homeostasis; Calcium signalling and zymogen granules exocytosis; autophagy; autoimmune pancreatitis related genes. Results: We detected mutations in 34 out of 70 genes examined; 64/80 patients (80.0%) were positive for mutations in one or more genes, 16/80 patients (20.0%) had no mutations. Mutations in CFTR were detected in 32/80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38/64 patients positive for mutations showed variants in two or more genes (59.3%). Conclusions: Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in chronic pancreatitis and that trans-heterozygosity may predispose to the idiopathic CP phenotype.
Authors: Els Dequeker; Manfred Stuhrmann; Michael A Morris; Teresa Casals; Carlo Castellani; Mireille Claustres; Harry Cuppens; Marie des Georges; Claude Ferec; Milan Macek; Pier-Franco Pignatti; Hans Scheffer; Marianne Schwartz; Michal Witt; Martin Schwarz; Emmanuelle Girodon Journal: Eur J Hum Genet Date: 2008-08-06 Impact factor: 4.246
Authors: Jaclyn R Bartlett; Kenneth J Friedman; Simon C Ling; Rhonda G Pace; Scott C Bell; Billy Bourke; Giuseppe Castaldo; Carlo Castellani; Marco Cipolli; Carla Colombo; John L Colombo; Dominique Debray; Adriana Fernandez; Florence Lacaille; Milan Macek; Marion Rowland; Francesco Salvatore; Christopher J Taylor; Claire Wainwright; Michael Wilschanski; Dana Zemková; William B Hannah; M James Phillips; Mary Corey; Julian Zielenski; Ruslan Dorfman; Yunfei Wang; Fei Zou; Lawrence M Silverman; Mitchell L Drumm; Fred A Wright; Ethan M Lange; Peter R Durie; Michael R Knowles Journal: JAMA Date: 2009-09-09 Impact factor: 56.272
Authors: Amanda H Mortensen; Qing Fang; Michelle T Fleming; Thomas J Jones; Alexandre Z Daly; Kenneth R Johnson; Sally A Camper Journal: Mamm Genome Date: 2019-02-18 Impact factor: 2.957
Authors: Ming Tan; Klaus Brusgaard; Anne-Marie Gerdes; Michael Bau Mortensen; Sönke Detlefsen; Ove B Schaffalitzky de Muckadell; Maiken Thyregod Joergensen Journal: Clin Genet Date: 2021-08-03 Impact factor: 4.296