Chronic Pancreatitis Panel

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). Mutations in several genes have been identified to be causative for, or induce susceptibility to pancreatitis (Joergensen et al. 2010). Genetic testing can aid in differential diagnosis of chronic pancreatitis from other disorders such as Shwachman-Diamond syndrome and Johanson-Blizzard syndrome which also present with pancreatitis (LaRusch et al. 2014).

Hereditary chronic pancreatitis (HP) occurs at an estimated incidence of 0.3/100,000 in western countries (Joergensen et al. 2010) and is inherited in an autosomal dominant manner through mutations in the PRSS1 gene in ~60% of cases. About 30% of HP results from inheritance with reduced penetrance through mutations in the SPINK1, CFTR, CTRC, and CASR genes (Masson et al. 2013; LaRusch et al. 2014).

PRSS1 encodes trypsinogen which becomes converted to active trypsin after secretion into the duodenum to aid in digestion. About 60% of HP cases are inherited in an autosomal dominant manner through mutations in the PRSS1 gene. Pathogenic mutations typically result in premature conversion of trypsinogen or resistance to degradation. Duplication in the PRSS1 gene resulting in elevated trypsinogen levels are also a reported cause to HP (Chen and Ferec et al. 2009; LaRusch et al. 2014).

SPINK1 encodes a pancreatic secretory trypsin inhibitor which protects the pancreas from damage due to recurrent or persistent trypsin activation (Horii et al. 1987). HP can be inherited in an autosomal recessive manner through SPINK1 mutations or more commonly through a possible digenic mode together with mutations in the CFTR and CTRC genes. Splice site alterations, gross deletions, and frameshift mutations are considered severe alleles with the highest penetrance in the SPINK1 gene. However, a moderate penetrant missense mutation, c.101A>G (p.Asn34Ser), is most commonly found within SPINK1 in European and North American populations. The c.194+2T>C variant is commonly found in Asian populations (LaRusch et al. 2014).

CFTR encodes a transmembrane conductance protein which functions to secrete bicarbonate fluid to flush pancreatic zymogens into the duodenum. HP can be inherited through an autosomal recessive manner through CFTR mutations but more commonly through a more complex mode together with mutations in the SPINK1 or CASR genes. CFTR mutations have been reported in the presence of PRSS1 mutations in a minor subset of HP patients (Masson et al. 2013).

CTRC encodes chymotrypsin C which degrades prematurely activated trypsinogen within the pancreas. To date, CTRC mutations have primarily been reported in HP patients with co-occurring CFTR mutations, but may co-occur with SPINK1 mutations. Loss of function mutations are primarily found in the CTRC gene in patients with HP (Masson et al. 2013).

CASR encodes a calcium sensing receptor that maintains calcium homeostasis. CASR mutation are low penetrant and are only found in HP patients together with CFTR or SPINK1 mutations (Whitcomb et al. 2013 Felderbauer et al. 2006).

For further information on PRSS1, SPINK1, CFTR, CTRC, or CASR genes please refer to the individual test descriptions.

About 48% of idiopathic chronic pancreatitis patients were found to display evidence of a genetic basis for their pancreatitis and carried at least one abnormal allele in one of the four genes, PRSS1, SPINK1, CFTR or CTRC (Masson et al. 2013).

Though rare, complete gene duplications have been reported for PRSS1-associated HP (Masson et al. 2008; Le Maréchal et al. 2006). To date, no gross duplications or deletions have been reported for CFTR-associated pancreatitis (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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. This test also includes sequencing of CFTR regions within intron 11 and intron 21, along with a complete analysis of the compound (TG)n(T)n sequence (5T/TG tract) in intron 8. Variations in the 5T/TG tract have been reported to cause CBAVD (Chillon et al. 1995). Our 5T/TG tract analysis involves bidirectional sequencing along with allele length measurement. We define 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).