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

Useful For

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

Method Name

Custom Sequence Capture and Targeted Next-Generation Sequencing (NGS) followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing when appropriate

Reporting Name

RET Gene, Full Gene Analysis

Specimen Type

Varies


Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Additional Information: To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.


Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time
Varies Ambient (preferred)
  Frozen 
  Refrigerated 

Clinical Information

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

An interpretive report will be provided.

Interpretation

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.

Clinical Reference

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/

Day(s) and Time(s) Performed

Performed weekly; Varies

Analytic Time

14 days

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81406-RET (ret proto-oncogene) (eg, Hirschsprung disease), full gene sequence

LOINC Code Information

Test ID Test Order Name Order LOINC Value
RETZ RET Gene, Full Gene Analysis 40693-4

 

Result ID Test Result Name Result LOINC Value
53108 Result Summary 50397-9
53109 Result 21733-1
53110 Interpretation 69047-9
53111 Additional Information 48767-8
53112 Specimen 31208-2
53113 Source 31208-2
53114 Released By 18771-6

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Inherited Cancer Syndromes Patient Information (T519) in Special Instructions

3. If not ordering electronically, complete, print, and send an Oncology Test Request Form (T729) with the specimen.

Mayo Clinic Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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