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Test Catalog

Test ID: HPPAN    
Hereditary Pancreatitis Panel, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Confirmation of suspected clinical diagnosis of familial or hereditary pancreatitis in patients with chronic pancreatitis

 

Identification of gene mutations contributing to pancreatitis in an individual or family

 

Identification of gene mutations to allow for predictive and diagnostic testing in family members

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes Sanger sequencing to evaluate for mutations in the PRSS1 gene, next-generation sequencing to evaluate for mutations in the CFTR, CTRC, and SPINK1 genes, and multiplex ligation-dependent probe amplification for the detection of large deletions and duplications within the CFTR gene.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Hereditary pancreatitis (HP) is defined as 2 or more individuals in a family affected with pancreatitis involving at least 2 generations. Mutations in several genes, including PRSS1, CFTR, CTRC, and SPINK1 have demonstrated genetic susceptibility to chronic pancreatitis. Disease susceptibility may be monogenic, as is the case with PRSS1, digenic or multigenic, and multifactorial in which multiple genes and environmental factors play a role in disease expression.

 

PRSS1:

The most common monogenic cause of HP is the presence of a mutation in the cationic trypsinogen (PRSS1) gene. Mutations in the PRSS1 gene are inherited in an autosomal dominant manner. It has been reported that as many as 80% of patients with symptomatic hereditary pancreatitis have a causative PRSS1 mutation. HP cannot be clinically distinguished from other forms of pancreatitis. However, PRSS1 mutations are generally restricted to individuals with a family history of pancreatitis and are infrequently found in patients with alcohol-induced or tropical pancreatitis. Although several mutations have been identified, the R122H, N29I, and A16V mutations are the most common disease-causing mutations in PRSS1 associated with HP. Data suggests that the R122H mutation results in more severe disease and earlier onset of symptoms than the A16V mutation. Patients with HP are also at an increased risk for developing pancreatic cancer. Studies have estimated the lifetime risk of developing pancreatic cancer to be as high as 40%.

 

SPINK1:

Biallelic mutations in the SPINK1 gene have been associated with increased susceptibility to chronic pancreatitis especially in families without PRSS1 mutations; however, it is unknown if biallelic mutations alone are sufficient to cause chronic pancreatitis. Additionally, heterozygous SPINK1 mutations appear to modify disease severity when observed in combination with mutations in other genes. Unlike PRSS1 mutations, SPINK1 mutations have been associated with alcohol-induced and tropical pancreatitis.

 

CFTR:

Pancreatitis is a known manifestation of an atypical CFTR-related disorder in which 2 mutations in the CFTR gene are identified. However, CFTR mutations can also co-occur with mutations in CTRC, SPINK1, or CASR to confer pancreatitis disease susceptibility. When observed in the context of a SPINK1 mutation, for example, heterozygous mutations in CFTR are associated with a 2- to 5-fold increased risk for pancreatitis as compared to the general population.

 

CTRC:

Mutations in CTRC have been observed in individuals with chronic pancreatitis in association with other risk factors such as mutations in CFTR or SPINK1 or specific environmental risk factors. Thus, chronic pancreatitis may be attributable to the presence of CTRC mutations in the context of other risk factors as opposed to CTRC mutations alone.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

All detected alterations will be evaluated according to the American College of Medical Genetics and Genomics (AMCG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Some individuals with a diagnosis of hereditary pancreatitis and/or involvement of the genes tested may have a mutation that is not identified by this method (eg, large genomic deletions or duplications, promoter mutations, deep intronic mutations). The absence of a mutation, therefore, does not eliminate the possibility of a diagnosis of hereditary pancreatitis or susceptibility to pancreatitis. For predictive testing of asymptomatic individuals, it is important to first document the presence of a gene mutation in an affected family member.

 

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

 

Technical limitations:

In some cases, DNA variants of undetermined significance may be identified.

 

Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

 

In addition to disease-related probes, the multiplex ligation-dependent probe amplification (MLPA) technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.

 

Evaluation tools:

Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently unvalidated.

 

Unless reported or predicted to cause disease, alterations in protein coding genes that do not result in an amino acid substitution are not reported. These and common polymorphisms identified for this patient are available upon request.

 

Reclassification of Variants-Policy:

All detected alterations are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. At this time, it is not standard practice for the laboratory to systematically review likely pathogenic alterations or variants of uncertain significance that have been previously detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424

2. Raphael KL, Willingham FF: Hereditary pancreatitis: current perspectives. Clin Exp Gastroenterol. 2016 Jul 26;9:197-207

3. Solomon S, Whitcomb DC: Genetics of pancreatitis: an update for clinicians and genetic counselors. Curr Gastroenterol Rep 2012;14(2):112-117

4. Ellis I: Genetic counseling for hereditary pancreatitis-the role of molecular genetics testing for the cationic trypsinogen gene, cystic fibrosis and serine protease inhibitor Kazal type 1. Gastroenterol Clin North Am 2004;33:839-854

5. Pancreatitis Overview. In GeneReviews-NCBI Bookshelf. 2014 Mar 13. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington,. Seattle WA. 1993-2018. Accessed January 2019. Available at URL: http://www.ncbi.nlm.nih.gov/books/NBK190101/

Special Instructions Library of PDFs including pertinent information and forms related to the test