Molecular genetic framework underlying pulmonary arterial hypertension


Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of high-throughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal-dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications for lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention.

Key points

  • Heterozygous germline mutations in BMPR2 represent the central susceptibility factor in the precipitation and progression of pulmonary arterial hypertension (PAH).

  • Causal rare disease alleles have been identified in both bone morphogenetic protein (BMP) signalling and non-BMP pathways, confirming locus heterogeneity in PAH.

  • Next-generation sequencing has been instrumental in expanding the genetic architecture of PAH by broadening the mutation spectrum in known genes and identifying novel genetic risk alleles.

  • Childhood-onset PAH is associated with greater morbidity and mortality than adult-onset disease and has a distinctive genetic signature.

  • PAH is a Mendelian disorder with complex disease traits, indicating a role for modifying common variation in disease development.

  • Elucidating the genetic architecture of PAH provides unprecedented potential for the development of novel, precision medicine options in disease management.

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Fig. 1: Major pathways and gene variants in heritable pulmonary arterial hypertension.


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L.S. is supported by the Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z) awarded to St George’s, University of London, UK. N.W.M. is supported by a British Heart Foundation Personal Chair Award.

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Correspondence to Nicholas W. Morrell.

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Southgate, L., Machado, R.D., Gräf, S. et al. Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol 17, 85–95 (2020).

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