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Pulmonary Arterial Hypertension (PAH) via the BMPR2 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8061 BMPR2 81406 81406,81405 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8061BMPR281406 81405(x1), 81406(x1) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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

  • Brett Deml, PhD

Clinical Features and Genetics

Clinical Features

Pulmonary arterial hypertension (PAH) is a progressive disease in which occlusion of small pulmonary arteries causes increasing resistance of blood flow through the pulmonary vasculature. This increase in resistance generates higher pressure in the right ventricle and eventually results in heart failure. Symptoms of PAH can include, in decreasing order of frequency: dyspnea, fatigue, syncope, chest pain, palpitation, and edema. Onset of PAH ranges significantly; however, the mean age of diagnosis is ~36 years (Rich et al. 1987. PubMed ID: 3605900). Penetrance in BMPR2-related PAH is incomplete and is significantly higher in females (~42%) than males (~14%) (Larkin et al. 2012. PubMed ID: 22923661). The estimated annual incidence of PAH is ~1-2 cases per 1,000,000 people per year (Gaine and Rubin. 1998. PubMed ID: 9729004).

Determining the molecular basis of PAH has important implications as other disorders that can present with PAH have nearly complete penetrance (hemorrhagic telangiectasia, pulmonary venoocclusive disease, and ischiocoxopodopatellar syndrome) or can be inherited in an autosomal recessive manner (pulmonary venoocclusive disease), which alters the risk to family members. Additionally, testing may be able to differentiate between idiopathic and heritable forms of PAH.

Genetics

The vast majority of heritable cases of PAH are caused by pathogenic variants in BMPR2, which is inherited in an autosomal dominant manner. A majority of these variants are loss-of-function (nonsense, frameshift, splicing); however, missense variants have also been reported. Indeed, the BMPR2 gene is intolerant to loss of function variants, but not missense, in the heterozygous state (https://gnomad.broadinstitute.org/gene/ENSG00000204217). Gross deletions in BMPR2 account for ~14-23% of cases (Cogan et al. 2006. PubMed ID: 16728714; Gräf et al. 2018. PubMed ID: 29650961). Pathogenic variants in BMPR2 are frequently absent from the gnomAD database, with the most common pathogenic variant in gnomAD (c.1750C>T, p.Arg584*) present in just 1 out of ~31,400 alleles (~0.003%) (https://gnomad.broadinstitute.org/variant/2-203420138-C-T). De novo BMPR2 variants have been documented in sporadic cases of PAH (Thomson et al. 2000. PubMed ID: 11015450); however, the proportion of individuals with de novo variants is currently unknown. Rarer causes of PAH include: isolated PAH (BMPR1B, CAV1, KCNA5, KCNK3, SMAD9, GDF2), ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension (TBX4), hereditary hemorrhagic telangiectasia (ACVRL1, ENG), and pulmonary venoocclusive disease (EIF2AK4).

BMPR2 is a member of the transforming growth factor-β (TGFβ) superfamily of signaling molecules. BMP signal transduction begins when a BMP ligand binds to a heterotetrameric complex of a type I receptor (ACVR1 or BMPR1B) and type II receptor (BMPR2). ENG also acts as a co-receptor with this heterotetrameric complex. The active type II receptor then transphosphorylates the type I receptor, which in turn phosphorylates the regulatory SMADs (SMAD1/5/8). The regulatory SMAD then associates with its co-Smad (SMAD4) and translocates to the nucleus to regulate target gene expression (Wang et al. 2014. PubMed ID: 25401122). Disruptions in this signaling cascade are believed to result in the loss of anti-proliferative effects resulting in increased proliferation and a lack of apoptosis in pulmonary arterial smooth muscle cells, which is an important pathological feature of PAH (Dewachter et al. 2009. PubMed ID: 19324947). Multiple animal models of Bmpr2 loss have been created. Homozygous knockout of Bmpr2 in mice is embryonic lethal (Song et al. 2005. PubMed ID: 16027259). Although, heterozygous knockout mice do not develop spontaneous PAH (Song et al. 2005. PubMed ID: 16027259), conditional loss of Bmpr2 in pulmonary vascular endothelial cells results in spontaneous PAH in about one-third of mice (Hong et al. 2008. PubMed ID: 18663089).

Clinical Sensitivity - Sequencing with CNV PGxome

In one study, ~68% of individuals with a family history of PAH had pathogenic variants in BMPR2 (Girerd et al. 2010. PubMed ID: 20056902). However, in sporadic cases of PAH, pathogenic variants in BMPR2 were found in ~15% (Girerd et al. 2010. PubMed ID: 20056902).

Testing Strategy

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

This panel provides full coverage of all coding exons of the BMPR2 gene 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Candidates for this test are patients with clinical findings consistent with pulmonary arterial hypertension in the absence of conditions known to predispose to it. Targeted testing is indicated for family members of patients who have a known pathogenic variant in BMPR2.

Gene

Official Gene Symbol OMIM ID
BMPR2 600799
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Pulmonary Arterial Hypertension AD 178600

Citations

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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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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.
Total Price: $
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