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The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families
Christopher J Grocock1, Vinciane Rebours, Myriam N Delhaye
1School of Cancer Studies, University of Liverpool, UCD Building, Daulby Street, Liverpool, UK.
Insights
The PRSS1 p.A16V mutation shows highly variable penetrance in pancreatitis, indicating a role in multigenic inheritance. This genetic factor influences pancreatitis predisposition within families.
Area of Science:
- Genetics
- Gastroenterology
- Hereditary Diseases
Background:
- Hereditary pancreatitis (HP) is often linked to mutations in the PRSS1 gene.
- The p.A16V variant in PRSS1 has been identified, but its clinical significance and phenotypic associations require further characterization.
Purpose of the Study:
- To investigate and characterize the clinical phenotypes associated with the p.A16V mutation in the PRSS1 gene.
- To understand the inheritance patterns and penetrance of the p.A16V mutation in families with pancreatitis.
Main Methods:
- Collected clinical and epidemiological data from ten families with the p.A16V PRSS1 mutation.
- Genotyped individuals for mutations in PRSS1, SPINK1, CFTR, and CTRC genes.
- Categorized families based on pancreatitis history: hereditary pancreatitis, idiopathic disease, or single-generation affected.
Main Results:
- Identified ten families with p.A16V mutations, affecting 22 individuals.
- Median age of pancreatitis onset was 10 years; observed exocrine failure, diabetes mellitus, and pancreatic cancer.
- Compared p.A16V pancreatitis cases with other PRSS1 mutations (p.R122H, p.N29I) and non-carriers, finding no significant differences.
Conclusions:
- The p.A16V mutation exhibits highly variable and family-dependent penetrance.
- This suggests that the p.A16V mutation contributes to a multigenic inheritance pattern for pancreatitis predisposition.
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 >or=2 cases in >or=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.
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