Genetics and precision genomics approaches to pulmonary hypertension

Abstract

Considerable progress has been made in the genomics of pulmonary arterial hypertension (PAH) since the 6th World Symposium on Pulmonary Hypertension, with the identification of rare variants in several novel genes, as well as common variants that confer a modest increase in PAH risk. Gene and variant curation by an expert panel now provides a robust framework for knowing which genes to test and how to interpret variants in clinical practice. We recommend that genetic testing be offered to specific subgroups of symptomatic patients with PAH, and to children with certain types of group 3 pulmonary hypertension (PH). Testing of asymptomatic family members and the use of genetics in reproductive decision-making require the involvement of genetics experts. Large cohorts of PAH patients with biospecimens now exist and extension to non-group 1 PH has begun. However, these cohorts are largely of European origin; greater diversity will be essential to characterise the full extent of genomic variation contributing to PH risk and treatment responses. Other types of omics data are also being incorporated. Furthermore, to advance gene- and pathway-specific care and targeted therapies, gene-specific registries will be essential to support patients and their families and to lay the foundation for genetically informed clinical trials. This will require international outreach and collaboration between patients/families, clinicians and researchers. Ultimately, harmonisation of patient-derived biospecimens, clinical and omic information, and analytic approaches will advance the field.

FIGURE 1

Approximate burden of rare variants (mutations) in genes associated with pulmonary arterial hypertension (PAH) among patients diagnosed at paediatric or adult age. Fewer paediatric than adult cases lack genetic explanation. Among paediatric cases, ∼15% have an identifiable de novo variant in a gene not represented in the figure nor inherited from a biological parent while few to no adult cases have this finding. The “other” category includes genes classified (table 1) as definitive for PAH as well as those with less definitive evidence. BMPR2: bone morphogenetic protein receptor 2; TBX4: T-box transcription factor 4; SOX17: SRY-box transcription factor 17; ABCC8: ATP binding cassette subfamily C member 8; ACVRL: activin receptor like 1; ENG: endoglin; GDF2: growth differentiation factor 2; SMAD9: Smad family member 9.

FIGURE 2

Example of approach to optimise precision approaches to subjects using genomic information (adapted from [38]). As gene-associated endotypes (endophenotypes) are determined, this information may be combined with various sources of omic-derived data, such as transcriptomics and proteomics. Efforts to incorporate exogenous sources of influence, such as environmental or other exposures should also be made. Subsequent integrative analytic approaches may reveal that individuals with similar endophenotype (including pulmonary arterial hypertension (PAH)-specific mutation) ultimately segregate into different clusters of disease profile. They may have a similar endophenotype, but be biologically distinct and have different disease profiles. This may ultimately improve precision approaches to populations of subjects as well as individuals. BMPR2: bone morphogenetic protein receptor 2; TBX4: T-box transcription factor 4; SOX17: SRY-box transcription factor 17; UMAP: uniform manifold approximation and projection. Created using BioRender.com.

FIGURE 3

Harmonisation of resources, biomedical reagents and information and analytic approaches must be achieved to truly advance the field.