Genes Tested

CASR, CEL, CFTR, CLDN2, CPA1, CTRC, PRSS1, SBDS, SPINK1, UBR1

PRSS1 deletion/duplication analysis by MLPA

Description

The Pancreas Panel is designed to establish the genetic causes of pancreatitis / pancreatic insufficiency or determine an individual’s risk of developing these conditions.

Pancreatitis is characterized by recurrent inflammation of the pancreas which can progress from acute to chronic. Pancreatic insufficiency is the inability of the pancreas to produce sufficient pancreatic digestive enzymes. It is commonly associated with pancreatitis and associated conditions. Chronic pancreatitis presents with mild-severe abdominal pain and exocrine pancreatic insufficiency, leading to digestive issues and endocrine pancreatic insufficiency. These conditions can lead to glucose intolerance / type I diabetes mellitus. Pancreatitis can occur as a part of a syndrome (for example Johanson Blizzard syndrome or Shwachman-Diamond syndrome (SBDS)) or as an isolated finding. It can be caused by underlying genetic factors or non-genetic environmental factors (e.g. alcohol abuse, infection or trauma) or a combination of both. Pancreatitis is usually categorized as hereditary, familial or idiopathic. Depending on the underlying genetic etiology, it can be inherited in autosomal dominant, autosomal recessive or in a polygenic manner.

Indications

  • Chronic pancreatitis of unknown etiology with overlapping clinical symptoms
  • Maturity-onset diabetes of the young, type VIII
  • Shwachman-Diamond syndrome
  • Johanson Blizzard syndrome
  • Presymptomatic diagnosis for at-risk individuals with a family history of pancreatitis of unknown genetic basis

Testing Methodology

This test is performed by enrichment of the coding exons, flanking intronic and untranslated regions (5’ and 3’), as well as known pathogenic variants (HGMD 2018.1) in the promoter and deep intronic regions of the genes specified above using oligonucleotide probe hybridization followed by next-generation sequencing with >50X coverage at every target base. All pathogenic and novel variants, as well as variants of unknown (indeterminate) significance, as determined bioinformatically, are confirmed by Sanger sequencing. Regions with <50X will be filled in by Sanger sequencing. A detailed non-coding variant list is available upon request. PRSS1 sequencing is performed by Sanger due to high homologous regions and PRSS1 deletion/duplication is included and performed by MLPA.

Test Sensitivity

One study identified that 48.2 percent of patients with idiopathic pancreatitis have evidence of a genetic basis for their pancreatitis (Masson et al. 2013). 60-100 percent of families with hereditary pancreatitis have single identifiable heterozygous pathogenic variant in the PRSS1 gene (LaRusch et al. 2011). Two common PRSS1 mutations in exon 2 and 3 account for approximately 90 percent of mutations observed in PRSS1-related hereditary pancreatitis (Rebours et al. 2009). Isolated pathogenic variants in CFTR, CTRC, and SPINK1 have been found to be associated with increased susceptibility to pancreatitis. Pancreatitis and subsequent pancreatic insufficiency are cardinal features in syndromes such as Johanson-Blizzard syndrome, Shwachman-Diamond syndrome and CEL maturity-onset diabetes of the young. Variants in CLDN2, CPA1, and CTRC act as risk modifiers for individuals with pancreatitis.

Analytical Sensitivity: The sensitivity of DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed.

Limitations: Variants in regulatory regions and non-reported variants in untranslated regions may not be detected by this test. Large deletions involving entire single exons or multiple exons, large insertions and other complex genetic events will not be identified using NGS methodology. Rare primer site variants may lead to erroneous results.

Turnaround Time

28 days

CPT Codes

81223, 81404 (x2), 81405, 81406, 81479 (x5)

How to Order

Download Heritable Pancreatic Disease requisition. Single gene sequencing and targeted variant analysis is also available for all genes in the Pancreas Panel. Deletion / duplication of PRSS1 is included with the Pancreas Panel. Targeted deletion/duplication analysis is available for all genes listed except CEL, CLDN2, CPA1, SBDS, and UBR1.

References

Koziel, D., S. Gluszek, et al. (2015) "Genetic Mutations in SPINK1, CFTR, CTRC Genes in Acute Pancreatitis." BMC Gastroenterology 15: 70.

LaRusch, J. and D. Whitcomb. (2011) "Genetics of pancreatitis." Curr Opin Gastroenterol 27(5): 467–474.

Masson, E., C. Le Marechal, et al. (2008) “Trypsinogen copy number mutations in patients with idiopathic chronic pancreatitis.” Clin Gastroenterol Hepatol 6(1): 82-8.

Ravi Kanth, V. and R. Nageshwar. (2014) "Genetics of acute and chronic pancreatitis: An update." World J Gastrointest Pathophysio 5(4): 427-37.

Whitcomb, D. (2013) "Genetic Risk Factors for Pancreatic Disorders." Gastroenterology 144(6): 1292–1302.