Pulmonary Arterial Hypertension (PAH) Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
12625 ACVRL1 81479,81479 Order Options and Pricing
BMPR1B 81479,81479
BMPR2 81406,81405
CAV1 81479,81479
EIF2AK4 81479,81479
ENG 81406,81405
GDF2 81479,81479
KCNA5 81479,81479
KCNK3 81479,81479
SMAD9 81479,81479
TBX4 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
12625Genes x (11)81479 81405, 81406, 81479 $890 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. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

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

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).

PAH can present with hereditary hemoragic telangictasia (HHT) or ischiocoxopodopatellar syndrome (ICPPS) (Girerd et al. 2010. PubMed ID: 20056902). Rarely, PAH can be present without signs of HHT, often early in the onset of disease (Fujiwara et al. 2008. PubMed ID: 18159113). Additionally, individuals with pulmonary venoocclusive disease (PVOD) can frequently be misdiagnosed as having PAH (Hadinnapola et al. 2017. PubMed ID: 28972005). Importantly, determining the molecular basis has implications in these cases as PVOD is recessive and the penetrance of HHT, PVOD, and ICPPS is complete or nearly complete. Additionally, testing may be able to differentiate between idiopathic and heritable forms of PAH.

Genetics

The great majority of heritable forms 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. Gross deletions in BMPR2 account for ~14-23% of cases (Cogan et al. 2006. PubMed ID: 16728714; Gräf et al. 2018. PubMed ID: 29650961). 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 (BMPR1B, CAV1, KCNA5, KCNK3, SMAD9, GDF2), ICPPS (TBX4), and HHT (ACVRL1, ENG) are all inherited in an autosomal dominant fashion, except for PVOD (EIF2AK4) which exhibits autosomal recessive inheritance.

BMPR2 is a member of the transforming growth factor-β (TGFβ) superfamily of signalling molecules. BMP signal transduction begins when a BMP ligand binds to a heterotetrameric complex of two type I receptors (ACVR1 or BMPR1B) and two type II receptors (BMPR2). Additionally, ENG acts as a co-receptor with this heterotetrameric receptor 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).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

In one study, ~68% of individuals with a family history of PAH had pathogenic variants in BMPR2, while ~5% of individuals had pathogenic variants in ACVRL1 (Girerd et al. 2010. PubMed ID: 20056902). However, in sporadic cases of PAH variants in BMPR2 and ACVRL1 were found in ~15% and ~2% of cases, respectively (Girerd et al. 2010. PubMed ID: 20056902). Pathogenic variants in several other genes (BMPR1B, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, SMAD9, TBX4) account for a small minority of PAH (~1-3%) (Gräf et al. 2018. PubMed ID: 29650961; Southgate et al. 2020. PubMed ID: 31406341).

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 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

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.

Genes

Official Gene Symbol OMIM ID
ACVRL1 601284
BMPR1B 603248
BMPR2 600799
CAV1 601047
EIF2AK4 609280
ENG 131195
GDF2 605120
KCNA5 176267
KCNK3 603220
SMAD9 603295
TBX4 601719
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
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Hereditary Hemorrhagic Telangiectasia (HHT)/Osler-Weber-Rendu Disease, and Capillary Malformation-Arteriovenous Malformation Syndrome (CM)-AVM Panel
Small Patella Syndrome via the TBX4 Gene

Citations

  • Cogan et al. 2006. PubMed ID: 16728714
  • Dewachter et al. 2009. PubMed ID: 19324947
  • Fujiwara et al. 2008. PubMed ID: 18159113
  • Gaine and Rubin. 1998. PubMed ID: 9729004
  • Girerd et al. 2010. PubMed ID: 20056902
  • Gräf et al. 2018. PubMed ID: 29650961
  • Hadinnapola et al. 2017. PubMed ID: 28972005
  • Larkin et al. 2012. PubMed ID: 22923661
  • Rich et al. 1987. PubMed ID: 3605900
  • Southgate et al. 2019. PubMed ID: 31406341
  • Thomson et al. 2000. PubMed ID: 11015450
  • Wang et al. 2014. PubMed ID: 25401122

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

View Ordering Instructions

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.

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