Chronic Pancreatitis via the Chymotrypsin C (CTRC) Gene

Pancreatitis is characterized by recurrent episodes of inflammation of the pancreas in both adults and children (Chen, J.M. and Ferec, C. Annu Rev Genomics Hum Genet 10:63-87, 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, V. et al. Dig Liver Dis 44(1):8-15, 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, D. and Whitcomb, D.C. Nat Rev Gastroenterol Hepatol 7(3):131–145, 2010). Mutations in several genes have been identified to be causative for or induce susceptibility to pancreatitis (Joergensen, M.T. et al. Am J Gastroenterol 105(8):1876-1883, 2010).

Hereditary chronic pancreatitis (HP) occurs at an estimated incidence of 0.3/100,000 in western countries (Joergensen, M.T. et al., 2010) and presents as autosomal dominant or recessive with incomplete penetrance (80%) depending upon the gene that is involved. Mutations in the Chymotrypsin C (CTRC) gene are known to increase susceptibility to chronic pancreatitis and are inherited in a digenic mode (heterozygous mutations along with mutations in other genes such as SPINK1 or CFTR) or as autosomal recessive (Masson, E. et al. PLoS One 8(8):e.73522, 2013).

The CTRC gene encodes a protease that functions to prevent premature trypsinogen activation in the pancreas as well as promote trypsin degradation (Szmola, R. and Sahin-Toth, M. PNAS 104(27): 11227–11232, 2007). Loss-of-function mutations in CTRC predispose to pancreatitis (Rosendahl, J. et. al. Nat Genet 40(1):78-82, 2008). Types of mutations reported in CTRC include missense, splicing, regulatory, deletion and insertion variants (Human Gene Mutation Database).

Our full gene sequencing test is expected to detect >98% of CTRC causative mutations.

This test provides full coverage of all coding exons of the CTRC 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).