Pulmonary Arterial Hypertension (PAH) via the BMPR2 Gene

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.

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).

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).

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).