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Test Catalog

Test ID: RETZ    
RET Proto-Oncogene, Full Gene Analysis, Varies

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

Confirmation of suspected clinical diagnosis of multiple endocrine neoplasia type A or B, Hirschsprung disease, or congenital central hypoventilation syndrome

 

Identification of familial pathogenic or likely pathogenic RET mutation to allow for predictive or 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 next-generation sequencing of exons 1-20 to evaluate for mutations in the RET gene. Sanger sequencing may be performed to confirm detected variants. Testing can be ordered for multiple endocrine neoplasia types 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). If an interpretation is desired specific to Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS), call 800-533-1710 and ask for the Genomics Genetic Counselor oncall.

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

Mutations in the RET proto-oncogene are associated with 3 distinct, and in rare cases, overlapping clinical syndromes.

 

Multiple endocrine neoplasia type 2 (MEN2):

MEN2 is an autosomal dominant cancer syndrome that has classically been divided into 3 subtypes: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). The characteristic features of MEN 2A include medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism. MEN 2B is characterized by early-onset MTC, pheochromocytoma, mucosal neuromas, and distinctive facies with enlarged lips. Other features of MEN 2B include enlarged nerves of the gastrointestinal tract (ganglioneuromatosis), marfanoid habitus, hypotonia, and corneal nerve thickening. FMTC has traditionally been diagnosed in families with 4 or more cases of MTC in the absence of pheochromocytoma or parathyroid involvement. Early diagnosis of thyroid cancer and appropriate surgical intervention can prevent metastatic MTC and can reduce the morbidity and mortality associated with MTC. All MEN2 subtypes are inherited in an autosomal dominant inheritance pattern. The majority of MEN2-related mutations occur at conserved cysteine residues within exons 10 and 11. Additional mutations in exons 13, 14, 15, and 16 account for the majority of other MEN2-related RET mutations.

 

Hirschsprung disease (HSCR):

HSCR is a congenital disorder of impaired intestinal motility, also known as aganglionic megacolon. Variable lengths of the colon may be affected, resulting in either total aganglionosis, long-segment HSCR, or short-segment HSCR. HSCR affects approximately 1 in 5,000 live births and is resolved via surgical intervention.

 

Hirschsprung disease can result from chromosome abnormalities, single gene disorders (both syndromic and non-syndromic), a combination of mutations in multiple genes, and unknown causes. Pathogenic RET variants are considered the most common cause of HSCR cases, though, particularly in families with multiple cases of HSCR and long segment disease. It has been reported that up to 50% of familial cases of HSCR and 3% to 10% of single HSCR cases are due to RET germline mutations.

 

While gain of function mutations in RET are typically associated with MEN2, loss of function mutations have been reported in patients with Hirschsprung disease (HSCR) including full or partial RET gene deletions. In addition to clearly pathogenic RET variants that cause HSCR, additional benign variants in RET (which may not be causative in themselves) confer increased susceptibility to HSCR.

 

Congenital central hypoventilation syndrome (CCHS):

CCHS is a congenital disorder of autonomic nervous system dysfunction in which individuals hypoventilate during sleep, and less commonly while awake. While not the primary etiology of disease, RET mutations have been associated with CCHS; in addition, RET mutations may be modifiers of CCHS development in individuals with HSCR.

 

Co-occurrence of HSCR and CCHS is more commonly observed than the co-occurrence of MEN2 with either HSCR or CCHS.

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 American College of Medical Genetics and Genomics (ACMG) 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 who have a diagnosis of multiple endocrine neoplasia type A or B, Hirschsprung disease, or congenital central hypoventilation syndrome and/or involvement of RET 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 multiple endocrine neoplasia type A or B, Hirschsprung disease, or congenital central hypoventilation syndrome. Note that while full or partial gene RET deletions have been described in cases of Hirschsprung disease (HSCR), multiple endocrine neoplasia (MEN)/familial medullary thyroid carcinoma (FMTC2) occurs through a gain of function mechanism, gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications is not indicated for assessment of MEN2 and FMTC.

 

For predictive testing of asymptomatic individuals, it is important to first document the presence of an RET gene mutation in an affected family member.

 

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

 

Technical limitations:

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.

 

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.

 

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.

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. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, Evans DB, et al: Medullary thyroid cancer: management guidelines of the American Thyroid Association. 2009;19(6):565-612

3. Moline J, Eng C: Multiple endocrine neoplasia type 2: an overview. Genet Med 2011;13(9):755-764

4. Ruiz-Ferrer M, Fernandez RM, Antinolo G, et al: A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes. Genet Med 2006;8(11):704-710

5. de Pontual L, Pelet A, Trochet D, et al: Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus. J Med Genet 2006 May;43(5):419-423

6. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, et al: An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med 2010 Mar 15;181(6):626-644

7. Marquard J, Eng C. Multiple Endocrine Neoplasia Type 2-In GeneReviews-NCBI Bookshelf. Updated 2015 Jun 25. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington,. Seattle WA. 1993-2018. Accessed January 2019. Available at www.ncbi.nlm.nih.gov/books/NBK1257/

8. Parisi M. Hirschsprung Disease Overview. In -GeneReviews-NCBI Bookshelf. Updated 2015 Oct 1. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington,. Seattle WA. 1993-2017. Accessed January 2019. Available at www.ncbi.nlm.nih.gov/books/NBK1439/

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