Massively Parallel Sequencing/Sequencing
- Use for individuals with a personal history of idiopathic pancreatitis
- Use to detect sequence variants in the CFTR, CTRC, PRSS1, and SPINK1 genes
Multiplex Ligation-dependent Probe Amplification
- A copy of the family member's test result is required and a control sample from the affected family member is highly recommended.
- May be ordered to assess for large deletions/duplications in a gene of interest when a previous sequencing result was not diagnostic
Pancreatitis is a relatively common disorder with multiple etiologies that causes inflammation in the pancreas. Acute pancreatitis (AP) is a result of sudden inflammation, and patients may present with increased pancreatic enzyme concentrations. Chronic pancreatitis (CP) is a syndrome of progressive inflammation that may lead to permanent damage to pancreatic structure and function. Genetic testing can be utilized to determine a genetic cause of idiopathic or hereditary AP or CP and/or to assess risk of disease in family members.
Symptoms and Etiology
- CFTR (NM_000492), CTRC (NM_007272), PRSS1 (NM_002769), SPINK1 (NM_003122)
- PRSS1: autosomal dominant with gain-of-function variants
- CFTR, CTRC, SPINK1: autosomal recessive/digenic
This test is performed using the following sequence of steps:
- Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
- Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline.
- Sanger sequencing is performed as necessary to fill in regions of low coverage or known low quality, and in certain other situations to confirm variant calls.
|Variant Class||Analytical Sensitivity (PPA) Estimatea (%)
and 95% Credibility Region (%)
|Analytical Specificity (NPA) (%)|
Deletions 1-10 bpb
Insertions 1-10 bpb
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.
bVariants greater than 10 bp may be detected, but the analytical sensitivity may be reduced.
bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants
One of the following:
|Negative||No pathogenic variants detected in any of the genes; reduces the risk for hereditary pancreatitis but genetic etiology is not excluded|
|Uncertain||Variant(s) of uncertain clinical significance detected; may be disease-causing or benign|
- A negative result does not exclude a genetic etiology for pancreatitis.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of targeted genes
- Regulatory region and deep intronic variants other than 5T (IVS8), c.1680-886A>G (c.1679+1.6kbA>G), and c.3718-2477C>T in the CFTR gene
- Large deletions/duplications in any of the tested genes
- Variants in currently unknown genes that may be associated with pancreatitis
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Noncoding transcripts
- Low-level somatic variants
- Certain other variants due to technical limitations in the presence of pseudogenes or repetitive/homologous regions
Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.
Shelton C, LaRusch J, Whitcomb DC. Pancreatitis overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle; 1993-2022. [Updated: Jul 2020; Accessed: Feb 2022]
Shelton C, Solomon S, LaRusch J, et al. PRSS1-related hereditary pancreatitis. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington, Seattle; 1993-2020. [Last Update: Apr 2019; Accessed: Feb 2022]
Rebours V, Boutron-Ruault MC, Schnee M, et al. The natural history of hereditary pancreatitis: a national series. Gut. 2009;58(1):97-103.
Masson E, Chen JM, Audrézet MP, et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013;8(8):e73522.
LaRusch J, Whitcomb DC. Genetics of pancreatitis. Curr Opin Gastroenterol. 2011;27(5):467-474.
Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1252-1261.