Pulmonary Arterial Hypertension (PAH) Panel

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.

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.

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).

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. 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).