Chronic Hereditary Pancreatitis via the CPA1 Gene

Pancreatitis is characterized by recurrent episodes of inflammation of the pancreas in both adults and children (Chen and Ferec 2009). Symptoms usually begin in late childhood with an episode of acute pancreatitis and include severe upper abdominal burning pain radiating to the back, nausea, and vomiting that is worsened with eating (acute pancreatitis). Recurrent acute pancreatitis leads to chronic pancreatitis due to persistent inflammation. Chronic pancreatitis usually develops by early adulthood in affected individuals and symptoms include occasional or frequent abdominal pain of varying severity, flatulence, and bloating. Unexplained weight loss may occur from a lack of pancreatic enzymes hindering digestion (Rebours et al. 2012). Episodes of pancreatitis can lead to permanent tissue damage and loss of pancreatic function. Chronic pancreatitis increases the risk for diabetes and pancreatic cancer, more so with smoking and use of alcohol (Yadav and Whitcomb 2010). Causative mutations in several genes have been identified in pancreatitis (Joergensen et al. 2010; Witt et al. 2013).

Hereditary chronic pancreatitis (HP) occurs at an estimated incidence of 0.3/100,000 in western countries (Joergensen et al. 2010) and presents as autosomal dominant or recessive with incomplete penetrance (80%) depending upon the gene that is involved. Loss of function mutations in the caboxypeptidase A1 (CPA1) gene are known to be causative for HP, particularly early onset disease (Witt et al. 2013). Association of CPA1 with HP is a recent finding and studies have not been done to determine mode of inheritance accurately. However, the presence of heterozygous variants in affected individuals suggests an autosomal dominant mode of inheritance (Witt et al. 2013). The CPA1 gene encodes the pancreatic enzyme carboxypeptidase A1 which helps digestion of food in the pancreas via inhibition of zymogens. The types of mutations reported in CPA1 predominantly include missense, but also include nonsense, splicing, deletion and insertion variants (Human Gene Mutation Database). Mutations in PRSS1, SPINK1, CFTR, CASR and CTRC are also known to be involved in the onset of HP (Audrezet, M.P. et al. 2002).

In a single large cohort study, functionally impaired CPA1 variants were present in 29/944 (3.1%) German cases and 5/3,938 (0.1%) controls (odds ratio (OR) = 24.9), 8/600 (1.3%) cases and 9/2,432 (0.4%) controls from Europe (P = 0.01), 5/230 (2.2%) cases and 0/264 controls from India (P = 0.02) and 5/247 (2.0%) cases and 0/341 controls from Japan (P = 0.013). The association was strongest in subjects aged ≤10 years (9.7%; OR = 84.0, P = 4.1 × 10−24) (Witt et al. 2013).

This test provides full coverage of all coding exons of the CPA1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).