Test Code HPGLP Hereditary Paraganglioma/Pheochromocytoma Panel, Varies

Ordering Guidance

Customization of this panel and single gene analysis for any gene present on this panel are available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. For more information see FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

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. For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.

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 whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated

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.

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:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Inherited Cancer Syndromes Patient Information Sheet (T519)

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

Secondary ID

614579

Useful For

Evaluating patients with a personal or family history suggestive of a hereditary paraganglioma and pheochromocytoma (PGL/PCC) syndrome

Establishing a diagnosis of a hereditary PGL/PCC, allowing for targeted surveillance based on associated risks

Identifying genetic variants associated with increased risk for PGL/PCC, allowing for predictive testing and appropriate screening of at-risk family members

Special Instructions

Method Name

Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing.

Reporting Name

Hereditary PGL/PCC Panel

Specimen Type

Varies

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type	Temperature	Time	Special Container
Varies	Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

Paragangliomas (PGL)and pheochromocytomas (PCC) are rare neuroendocrine tumors that arise from autonomous ganglia. Tumors located within the adrenal medulla (the largest sympathetic ganglion) are called pheochromocytomas, while those that stem from either parasympathetic or sympathetic ganglia are designated paragangliomas.

PGL/PCC have a germline genetic basis in up to 30% of cases.(1) The genes implicated in hereditary PGL/PCC syndrome include MAX, TMEM127, FH, and the SDHx genes.

The genes most frequently associated with hereditary PGL/PCC syndromes are the succinate dehydrogenase-associated genes SDHA, SDHAF2, SDHB, SDHC, and SDHD.

Germline alterations in the MAX gene are typically associated with increased risk for PCC, although some individuals have been identified with PGL. MAX variants occur in approximately 1% of patients with hereditary PGL/PCC syndromes.(2)

TMEM127 variants are associated most commonly with PCC and rarely PGL.(1) Alterations of TMEM127 account for approximately 2% of individuals with hereditary PGL/PCC.(2)

Recent evidence suggests that disease-causing variants in FH also increase risk for PGL/PCC.(3,4) Individuals with disease-causing FH variants carry a significantly increased risk for cutaneous or uterine leiomyomata and renal tumors.(5)

Alterations in VHL, NF1, and RET also increase risk for PGL/PCC, in addition to other types of tumors.(6)

Disease-causing variants in the VHL gene are associated with a syndrome called von Hippel Lindau (VHL) syndrome. In addition to PGL/PCC, individuals with VHL syndrome are at increased risk for hemangioblastomas, renal cell carcinoma, pancreatic cysts, neuroendocrine tumors, endolymphatic sac and epididymal tumors.(7)

NF1 gene variants are associated with neurofibromatosis type I (NF1). Individuals with NF1 are at increased risk for pheochromocytomas in addition to neurofibromas and central nervous system gliomas, such as optic nerve gliomas. NF1 is also characterized by other features such as cafe-au lait macules, axillary/inguinal freckling and Lisch nodules.(8)

Disease-causing RET variants result in a syndrome called multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid cancer (FMTC). In addition to an increased risk for PGL/PCC, individuals with MEN2/FMTC have a very high risk of developing medullary thyroid cancer. Individuals with MEN2 may also have other features, such as primary hyperparathyroidism, mucosal neuromas, ganglioneuromatosis, and distinctive facial features.(9)

The National Comprehensive Cancer Network and the American Cancer Society provide recommendations regarding the medical management of individuals with hereditary PGL/PCC syndromes.(10)

Reference Values

An interpretive report will be provided.

Interpretation

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(11) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Method Description

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletion-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed..

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. For details regarding the targeted genes analyzed or specific gene regions not routinely covered see Targeted Genes and Methodology Details for Hereditary Paraganglioma/Pheochromocytoma.(Unpublished Mayo method)

Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

Genes analyzed: FH, MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, and VHL

Day(s) Performed