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Hereditary Pancreatitis Gene Panel

Hereditary pancreatitis is a rare autosomal dominant disorder that is characterized by early onset of acute pancreatitis during childhood or early adolescence and progression to chronic pancreatitis by adulthood. Patients with hereditary pancreatitis have a higher risk of developing pancreatic cancer. The diagnosis of hereditary pancreatitis is based upon clinical history and recognition of an inheritance pattern.

Cationic trypsin is the most abundant form of trypsin secreted by the pancreas into the duodenum. Trypsin converts pancreatic zymogens into digestive enzymes. Trypsin has two regulatory domains, one regulating cleavage of trypsinogen into trypsin and the other regulating inhibition of trypsin activity. Nearly all of the mutations associated with autosomal dominant hereditary pancreatitis affect these two regulatory domains. Abnormal trypsin molecules predispose to pancreatitis by prematurely activating digestive enzymes within the pancreas or interfering with inactivation of trypsin activity.

The protease serine 1 or cationic trypsinogen (PRSS1) gene is located on chromosome 7. Mutations in exons 2 and 3 of this gene are present in up to 80% of patients with hereditary pancreatitis unrelated to cystic fibrosis. The most commonly detected mutations are Arg122His (R122H), Asn29Ile (N29I), Ala16Val (A16V), and Arg122cys (R122C). The absence of a mutation does not eliminate the possibility of positive carrier status or the diagnosis of HP.

Chronic pancreatitis may also be inherited as an autosomal recessive disorder. Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) gene are most common cause of pancreatitis with or without the other manifestations of cystic fibrosis. Nearly 2000 different genetic variants in CFTR have been identified. Complete gene sequencing should be considered, especially if the patient has recurrent sinusitis or male infertility. Multiple family members may be affected.

Mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene are also associated with autosomal recessive pancreatitis. The SPINK1gene is expressed in pancreatic acinar cells and codes for pancreatic secretory trypsin inhibitor. Mutations in SPINK1 interfere with trypsin inhibition and predispose to pancreatitis. Patients with pancreatitis are often homozygous or compound heterozygous, possibly with a CFTR mutation. SPINK1 mutations are present in 2% of the general population, but less than 1 percent of carriers develop pancreatitis. Mutations in SPINK1 increase the risk for chronic pancreatitis about 12-fold over the general population.

Genetic testing is most commonly limited to the PRSS1, CFTR and SPINK1 genes. Testing should be considered in patients with pancreatitis and one or more of the following criteria

  • Unexplained pancreatitis as a child
  • Idiopathic chronic pancreatitis, especially with onset before age 25
  • Family history of recurrent pancreatitis or childhood pancreatitis
  • Relatives with known mutations associated with hereditary pancreatitis
  • Recurrent acute attacks of pancreatitis with no identifiable cause

Specimen requirement is a lavender top (EDTA) or yellow top (ACD) containing at least 3 mL of blood.

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