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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 DLST 81479,81479 Order Options and Pricing
FH 81405,81479
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 (13)81479 81403(x1), 81404(x4), 81405(x4), 81406(x2), 81408(x1), 81479(x14) $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 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn 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

  • Hannah Cox, PhD

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; Else et al. 2018. PubMed ID: 20301715).

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. PubMed ID: 22041710).

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 (Else et al. 2018. PubMed ID: 20301715).

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. PubMed ID: 20664475) and for the hereditary PGL/PCC syndrome it has been estimated at 1:25,000 to 1:50,000 (Welander et al. 2011. PubMed ID: 22041710).

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 also known by their syndromic names PGL1, PGL3, and PGL4. The next most commonly mutated gene is SDHA (PGL5), which encodes a catalytic subunit of succinate-ubiquinone oxidoreductase. Hereditary PGL/PCC syndrome presents variable expressivity and age-related penetrance. The nuclear genes SDHA, SDHB, SDHC, and SDHD 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 (mTORC1) and has an important role in cellular proliferation and cell death (Else et al. 2018. PubMed ID: 20301715).

Other genes causative for hereditary paraganglioma-pheochromocytoma syndrome include FH, NF1, VHL, RETMEN1, and DLST. NF1 encodes for the protein neurofibromin, which is a tumor suppressor that activates GTPase and controls cellular proliferation (Friedman. 2019. PubMed ID: 20301288). 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. PubMed ID: 21386872). The RET proto-oncogene is one of many receptor tyrosine kinases, cell-surface molecules that transduce signals for cell growth and differentiation via RET autophosphorylation and intracellular signaling (Santoro et al. 2004. PubMed ID: 15331579). MEN1 is a tumor suppressor gene involved in many vital processes, including transcriptional regulation, DNA replication, and DNA repair (Larsson et al. 1988. PubMed ID: 2894610; Lemos and Thakker. 2008. PubMed ID: 17879353). The FH gene is a tumor suppressor encoding fumurate hydratase, which is involved in the conversion of fumarate to L-malate in the tricarboxylic acid (Krebs) cycle (Maher. 2011. PubMed ID: 21071978; Sudarshan et al. 2007. PubMed ID: 17287871). The DLST gene encodes a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase that is involved in the tricarboxylic acid (Krebs) cycle (Remacha et al. 2019. PubMed ID: 30929736; Buffet et al. 2021. PubMed ID: 33180916). In vivo experimental studies suggest that loss of DLST catalytic activity leads to a high alpha-KG/fumarate ratio and accumulation of the oncometabolite 2-hydroxyglutaric acid (2HG; Remacha et al. 2019. PubMed ID: 30929736).

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. PubMed ID: 22041710). 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 (Else et al. 2018. PubMed ID: 20301715). 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. PubMed ID: 22452945). 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. PubMed ID: 21115163). 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. PubMed ID: 22041710). The clinical sensitivity of DLST and FH pathogenic variants in predisposition to PGL/PCC is unknown, but pathogenic variants in both of these genes have been previously reported (Castro-Vega et al. 2014. PubMed ID: 24334767; Remacha et al. 2019. PubMed ID: 30929736; Buffet et al. 2021. PubMed ID: 33180916).

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. PubMed ID: 16258955) and have also been reported less frequently in the SDHC, SDHD, and MAX genes.

Testing Strategy

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

This panel typically provides 99.9% 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
DLST 126063
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

  • Buffet et al. 2021. PubMed ID: 33180916
  • Burnichon et al. 2012. PubMed ID: 22452945
  • Cascón et al. 2006. PubMed ID: 16258955
  • Castro-Vega et al. 2014. PubMed ID: 24334767
  • Chen et al. 2010. PubMed ID: 20664475
  • Comino-Méndez et al. 2011. PubMed ID: 21685915
  • Else et al. 2018. 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
  • Friedman. 2019. 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
  • Larsson et al. 1988. PubMed ID: 2894610
  • Lemos and Thakker. 2008. PubMed ID: 17879353
  • Maher et al. 2011. PubMed ID: 21386872
  • Maher. 2011. PubMed ID: 21071978
  • Opocher and Schiavi. 2010. PubMed ID: 21115163
  • Remacha et al. 2019. PubMed ID: 30929736
  • Santoro et al. 2004. PubMed ID: 15331579
  • Sudarshan et al. 2007. PubMed ID: 17287871
  • Welander et al. 2011. 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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

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

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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