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The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families
  1. Christopher J Grocock1,
  2. Vinciane Rebours2,
  3. Myriam N Delhaye3,
  4. Åke Andrén-Sandberg4,
  5. Frank Ulrich Weiss5,
  6. Roger Mountford6,
  7. Matthew J Harcus1,
  8. Edyta Niemczyck1,
  9. Louis J Vitone1,
  10. Susanna Dodd1,
  11. Maiken Thyregod Jørgensen7,
  12. Rudolf W Ammann8,
  13. Ove Schaffalitzky de Muckadell7,
  14. Jane V Butler1,
  15. Phillip Burgess9,
  16. Bronwyn Kerr10,
  17. Richard Charnley11,
  18. Robert Sutton1,
  19. Michael G Raraty1,
  20. Jacques Devière3,
  21. David C Whitcomb12,
  22. John P Neoptolemos1,
  23. Philippe Lévy2,
  24. Markus M Lerch5,
  25. William Greenhalf1
  1. 1School of Cancer Studies, University of Liverpool, UCD Building, Daulby Street, Liverpool, UK
  2. 2Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie-Pancréatologie, Hôpital Beaujon, Clichy, France
  3. 3Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium
  4. 4Department of Surgery, Karolinska Institute, Stockholm, Sweden
  5. 5Department of Medicine A, Ernst-Moritz-Arndt Universität, Greifswald, Germany
  6. 6Mersey Regional Molecular Genetics Laboratory, Liverpool Women's Hospital, Liverpool, UK
  7. 7Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark
  8. 8Clinic of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
  9. 9Department of Surgery, Great Western Hospital, Swindon, UK
  10. 10Department of Clinical Genetics, St Mary's Hospital, Manchester, UK
  11. 11Hepato-Pancreato-Biliary Surgery Unit, Freeman Hospital, Newcastle upon Tyne, UK
  12. 12Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, USA
  1. Correspondence to Dr W Greenhalf, Division of Surgery and Oncology, University of Liverpool, 5th Floor, UCD Building, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA UK; greenhaf{at}liv.ac.uk

Abstract

Objective To characterise the phenotypes associated with the p.A16V mutation of PRSS1.

Design Clinical and epidemiological data were collected for any family in which a p.A16V mutation was identified, either referred directly to the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer or via a collaborator. DNA samples were tested for mutations in PRSS1, SPINK1, CFTR and CTRC.

Patients Participants were recruited on the basis of either family history of pancreatitis (acute or chronic) or the results of genetic testing. Families were categorised as having hereditary pancreatitis (HP), idiopathic disease or pancreatitis in a single generation. HP was defined as ≥2 cases in ≥2 generations.

Main outcome measures Onset of painful episodes of pancreatitis, death from pancreatic cancer, diagnosis of diabetes mellitus and exocrine pancreatic failure.

Results Ten families with p.A16V mutations were identified (22 affected individuals): six HP families, three with idiopathic disease and one with only a single generation affected. The median age of onset, ignoring non-penetrants, was 10 years (95% CI 5 to 25). There were eight confirmed cases of exocrine failure, four of whom also had diabetes mellitus. There were three pancreatic cancer cases. Two of these were confirmed as p.A16V carriers, only one of whom was affected by pancreatitis. Those with p.A16V pancreatitis were compared to affected individuals with p.R122H, p.N29I and no PRSS1 mutation. No significant differences were proven using logrank or Mann–Whitney U tests.

Conclusions Penetrance of p.A16V is highly variable and family dependent, suggesting it contributes to multigenic inheritance of a predisposition to pancreatitis.

  • Pancreas
  • chronic pancreatitis
  • polymorphic variation
  • pancreatic cancer
  • diabetes mellitus

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Footnotes

  • Funding The European Union (Rue de Le Roi, Brussels); Cancer Research UK, London, UK; The National Institute for Health Research, London, UK.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Scotland A Research Ethics Committee, MREC/04/0/010.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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