Hereditary Paraganglioma-Pheochromocytoma (PGL/PCC) Syndrome Panel

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
1329 FH 81405,81479 Order Options and Pricing
MAX 81479,81479
MEN1 81405,81404
NF1 81408,81479
RET 81406,81479
SDHA 81406,81479
SDHAF2 81479,81479
SDHB 81405,81479
SDHC 81405,81404
SDHD 81404,81479
TMEM127 81479,81479
VHL 81404,81403
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
1329Genes x (12)81479 81403, 81404, 81405, 81406, 81408, 81479 $540 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available.

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

CPT codes 81437 and 81438 can be used if analysis includes MAX, SDHB, SDHC, SDHD, TMEM127, and VHL.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome is a familial cancer syndrome that 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 can 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. 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 1:2500 to 1:6000 (Chen et al. 2010) and for the hereditary PGL/PCC syndrome it 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 pathogenic variants in three genes, (SDHD, SDHC, and SDHB), which are known by their syndromic names PGL1, PGL3, and PGL4. The next most commonly mutated gene is SDHA (PGL5), which encodes a catalytic subunit of the succinate-ubiquinone oxidoreductase. Hereditary PGL/PCC syndrome presents variable expressivity and age-related penetrance. SDHA, SDHB, SDHC, and SDHD are nuclear genes that 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. Pathogenic variants 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).

Pathogenic variants in MAX, SDHD, and SDHAF2 demonstrate parent-of-origin effects and generally cause disease only when inherited from the father. A proband with a hereditary PGL/PCC syndrome may have inherited it from a parent or have a de novo variant, although the latter’s frequency is not known. An individual who maternally inherits a MAX, SDHD, or SDHAF2 pathogenic variant has a low risk of developing disease; however, each of the individual's offspring is at a 50% risk of inheriting the disease-causing allele. An individual who paternally inherits an MAX, SDHD, or SDHAF2 pathogenic variant is at high risk of manifesting PGL/PCC. Germline predisposing pathogenic variants have also been found in the gene TMEM127, which is a negative regulator of mechanistic target of rapamycin and has an important role in cellular proliferation and cell death (Kirmani and Young 2012; Welander et al. 2011).

Other genes that are causative for hereditary paraganglioma-pheochromocytoma syndrome include FH, NF1, VHL, RET, and MEN1. NF1 encodes for the protein neurofibromin, which is a tumor suppressor that activates GTPase and controls cellular proliferation (Friedman 2012). The VHL gene is also a tumor suppressor. Inactivation of both alleles at the cellular level leads to abnormal activation of genes involved in hypoxia (Maher et al. 2011). The RET proto-oncogene is one of many receptor tyrosine kinases, a cell-surface molecule that transduce signals for cell growth and differentiation via RET autophosphorylation and intracellular signaling (Santoro 2004). MEN1 is a tumor suppressor gene whose gene product is involved in many vital processes, including transcriptional regulation, DNA replication, and DNA repair (Larsson et al. 1988; Lemos and Thakker 2008). The FH gene is thought to be a tumor suppressor encoding fumurate hydratase, which is involved in the conversion of fumurate to L-malate in the tricarboxylic acid (Krebs) cycle (Maher. 2011; Sudarshan et al. 2007).

See individual gene test descriptions for additional information on molecular biology of gene products.

Clinical Sensitivity - Sequencing with CNV PG-Select

Although the majority of hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome tumors are sporadic (non-familial), approximately 13% of all PGL/PCC tumors are caused by germline pathogenic variants in known PGL/PCC syndrome genes (Welander et al. 2011). Clinical sensitivity is dependent on tumor location. For the SDHB gene, pathogenic variants are detectable in up to 44% of hereditary PGL/PCC cases; pathogenic variants in the SDHC gene are detectable in up to 8% of PGL/PCC hereditary cases; pathogenic variants in the SDHA gene are detectable in up to 3% of hereditary PGL/PCC cases; and pathogenic variants in the SDHD gene are detectable in up to 50% of hereditary PGL/PCC cases (Kirmani and Young 2012). The clinical sensitivity for SDHAF2 and TMEM127 pathogenic variants is currently unknown. Germline pathogenic variants in the MAX gene have been estimated to be responsible for PCC/PGL in 1% of patients (Burnichon et al. 2012). In addition to the known PGL/PCC syndrome genes, germline pathogenic variants in a number of other genes may also predispose to PGL/PCC tumors (Opocher and Schiavi 2010). 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); they are seen less often in Carney triad and Carney–Stratakis syndrome and rarely in multiple endocrine neoplasia type 1 (MEN1; Welander et al. 2011). The clinical sensitivity of FH pathogenic variants in predisposition to PGL/PCC is unknown, but pathogenic FH variants been reported previously (Castro-Vega et al. 2014).

Hereditary paraganglioma-pheochromocytoma syndrome deletion and duplication frequencies for the majority of these genes are unknown; however, deletions have been reported in the SDHB gene in 12% of patients (Cascón et al. 2006) and have also been reported less frequently in the SDHC, SDHD, and MAX genes (Burnichon et al. 2009).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

 

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. 

 

In addition to the regions described above, this testing includes coverage of the following variants that reside in deep intronic regions: PCCA c.1285-1416A>G and PCCB c.654+462A>G.

Indications for Test

Individuals with a clinical or family history of hereditary PGL/PCC syndrome should be tested early. Early 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.

Genes

Official Gene Symbol OMIM ID
FH 136850
MAX 154950
MEN1 613733
NF1 613113
RET 164761
SDHA 600857
SDHAF2 613019
SDHB 185470
SDHC 602413
SDHD 602690
TMEM127 613403
VHL 608537
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Burnichon N. et al. 2012. Clinical Cancer Research. 18: 2828-37. PubMed ID: 22452945
  • Cascón Alberto et al. 2006. Genes, Chromosomes and Cancer. 45: 213-219. PubMed ID: 16258955
  • Castro-Vega .LJ. et al. 2014. Human Molecular Genetics. 23: 2440-6. PubMed ID: 24334767
  • Chen H. et al. 2010. Pancreas. 39: 775-83. PubMed ID: 20664475
  • Comino-Méndez Iñaki et al. 2011. Nature Genetics. 43: 663-667. PubMed ID: 21685915
  • Friedman J. 2012. Neurofibromatosis 1. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301288
  • 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
  • Larsson C. et al. 1988. Nature. 332: 85-7. PubMed ID: 2894610
  • Lemos M.C., Thakker R.V. 2008. Human Mutation. 29: 22-32. PubMed ID: 17879353
  • Maher E.R. 2011. Nephron. Experimental Nephrology. 118: e21-6. PubMed ID: 21071978
  • Maher E.R. et al. 2011. European Journal of Human Genetics : Ejhg. 19: 617-23. PubMed ID: 21386872
  • Opocher G., Schiavi F. 2010. Best Practice & Research. Clinical Endocrinology & Metabolism. 24: 943-56. PubMed ID: 21115163
  • Santoro M. et al. 2004. Endocrinology. 145: 5448-51. PubMed ID: 15331579
  • Sudarshan S. et al. 2007. Nature Clinical Practice. Urology. 4: 104-10. PubMed ID: 17287871
  • Welander J. et al. 2011. Endocrine Related Cancer. 18: R253-R276. PubMed ID: 22041710

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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