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Hereditary Paraganglioma-Pheochromocytoma Syndrome via the MAX Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1138 MAX$610.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Approximately 13% of PGL/PCC tumors result from hereditary PGL/PCC syndrome (Welander et al. 2011). Germline mutations in MAX have been estimated to be responsible for PCC/PGL in 1% of patients (Burnichon et al. 2012). PGL/PCC tumors can also be found in 10% of other familial syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel–Lindau disease (VHL), and neurofibromatosis type 1 (NF1), and less so in Carney triad, Carney–Stratakis syndrome, and, very rarely, multiple endocrine neoplasia type 1 (MEN1) (Welander et al. 2011). The majority of PGL/PCC tumors are sporadic (i.e. non-familial), but up to 45% of PGL/PCC tumors may have germline mutations in a variety of genes (Opocher and Schiavi 2010).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 MAX$690.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity
The clinical sensitivity of deletion and duplications of the MAX gene in Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes is currently unknown; however a large deletion has been reported (Burnichon et al. 2012).

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Clinical Features
Hereditary Paraganglioma-Pheochromocytoma (PGL/PCC) syndrome is a familial cancer syndrome which results in neuroendocrine tumors. The diagnosis of hereditary PGL/PCC syndrome is based on physical examination, family history, imaging studies, biochemical testing, and molecular genetic testing. Symptoms of PGL/PCC result either from mass effects or catecholamine hypersecretion (e.g. sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, palpitations, pallor, and apprehension or anxiety) (Kirmani and Young 2012). Paraganglia are a group of neuroendocrine cells that originate from the embryonic neural crest and have the ability to secrete catecholamines. In PGL/PCC syndrome, paraganglia arise in either the paravertebral axis (base of the skull to the pelvis) for paragangliomas or the adrenal medulla for pheochromocytomas (Welander et al. 2011). Sympathetic paragangliomas hypersecrete catecholamines, whereas parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the head and neck and most often are nonsecretory. The sympathetic extra-adrenal paragangliomas are generally located in the thorax, abdomen, and pelvis, and are usually secretory. Pheochromocytomas typically hypersecrete catecholamines (Kirmani and Young 2012). The prevalence of PGL/PCC tumors in the United States has been estimated to be between 1:2,500 to 1:6,000 (Chen et al. 2010), and for the hereditary PGL/PCC syndrome has been estimated at 1:25,000 to 1:50,000 (Welander et al. 2011).
Genetics
Hereditary Paraganglioma-Pheochromocytoma syndrome is an autosomal dominant disorder and is mainly caused by mutations in three genes, SDHD, SDHC, and SDHB, which are known by their syndromic names PGL1, PGL3, and PGL4, respectively. Hereditary PGL/PCC syndrome presents variable expressivity and age-related penetrance. SDHA, SDHB, SDHC, and SDHD are nuclear genes which encode the four subunits of the mitochondrial enzyme succinate dehydrogenase (SDH). Another gene, SDHAF2 (also known as SDH5) encodes a protein that appears to be required for flavination of the SDHA subunit. Mutations in the MAX gene, which encodes a transcription factor that regulates cell proliferation, differentiation, and apoptosis, can also predispose individuals to PGL and PCC (Comino-Méndez et al. 2011; Burnichon et al. 2012). Mutations in MAX demonstrate parent-of-origin effects and generally cause disease only when the mutation is inherited from the father. A proband with a hereditary PGL/PCC syndrome may have inherited the mutation from a parent or have a de novo mutation. An individual who inherits a MAX mutation from his/her mother has a low risk of developing disease; each of his/her offspring is at a 50% risk of inheriting the disease-causing allele. An individual who inherits an MAX mutation from his/her father is at high risk of manifesting pheochromocytomas and less commonly paragangliomas (Kirmani and Young 2012; Welander et al. 2011).
Testing Strategy
The protein max is encoded by 5 exons from the MAX gene on chromosome 14q23. Testing is accomplished by amplifying each coding exon and ~20 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard Sanger dideoxy sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
Individuals with a history of Hereditary PGL/PCC syndrome. People with a family history of Hereditary PGL/PCC syndrome should be tested early (i.e. <10 years of age). Hereditary PGL/PCC syndrome should be considered in all individuals with paragangliomas and/or pheochromocytomas, especially those with multiple, multifocal, recurrent or early onset tumors (i.e. <40 years) (Young. 2008). This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

Earlier diagnosis may improve patient prognosis through regular screening and treatment for early-onset malignancies. Early detection through surveillance and removal of tumors may prevent or minimize complications related to mass effects, catecholamine hypersecretion, and malignant transformation.

Gene

Official Gene Symbol OMIM ID
MAX 154950
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Pheochromocytoma 171300

Related Tests

Name
Hereditary Paraganglioma-Pheochromocytoma Syndrome via the SDHA Gene
Hereditary Paraganglioma-Pheochromocytoma Syndrome via the SDHAF2 Gene

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, Inglada-Perez L, Cubas AA de, Amar L, Barontini M, Quiros SB de, Bertherat J, et al. 2012. MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma. Clinical Cancer Research 18: 2828–2837. PubMed ID: 22452945
  • Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K. 2010. The North American Neuroendocrine Tumor Society Consensus Guideline for the Diagnosis and Management of Neuroendocrine Tumors: Pheochromocytoma, Paraganglioma, and Medullary Thyroid Cancer. Pancreas 39: 775–783. PubMed ID: 20664475
  • Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, Landa I, Leandro-García LJ, Letón R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gómez-Graña Á, Cubas AA de, et al. 2011. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nature Genetics 43: 663–667. PubMed ID: 21685915
  • Kirmani S, Young WF. 2012. Hereditary Paraganglioma-Pheochromocytoma Syndromes. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301715
  • Opocher G, Schiavi F. 2010. Genetics of pheochromocytomas and paragangliomas. Best Practice & Research Clinical Endocrinology & Metabolism 24: 943–956. PubMed ID: 21115163
  • Welander J, Soderkvist P, Gimm O. 2011. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine Related Cancer 18: R253–R276. PubMed ID: 22041710
  • Young. Williams Textbook of Endocrinology, 11 ed. pp.:505-537, 2008
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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