Researchers described a new technique that could identify genetic alterations implicated in the pathogenesis of pulmonary arterial hypertension (PAH). The technique could identify aberrations not detectable with standard cytogenetic and molecular genetic tests.

This could enable tailored genetic counseling to be offered to patients and families with PAH as well as other lung diseases such as familial idiopathic pulmonary fibrosis (IPF) and the possible use of targeted gene therapies in the future.

PAH can either be inherited or be caused by other diseases such as connective tissue diseases, liver disease, congenital heart disease, or HIV. In the case of heritable PAH, mutations in the BMPR2 gene, which codes for bone morphogenic protein receptor type II, are the most common cause of the disease.

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In a recent study published in the journal Pulmonary Circulation researchers from Mayo Clinic College of Medicine in Rochester, Minnesota, led by Mark E. Wylam, MD, presented the case of a 36-year-old woman with PAH confirmed by right heart catheterization. 

The woman had a family history of the disease, with her sister, mother, maternal cousin, and second cousin all also having the disease. She did not have a secondary cause of PAH.

The researchers sequenced the woman’s BMPR2 gene as well as 8 other genes associated with the bone morphogenic protein pathway but could not find any genetic alterations that could explain her disease. Similarly, they could not see any abnormalities following deletion/duplication analyses or chromosomal analyses.

Then the researchers used a technique called pre-transplant mate-pair sequencing (MPseq) to further analyze the patient genetically. This approach revealed a cryptic paracentric inversion on chromosome 2 with breakpoints within intron 10 of the BMPR2 gene and intron 6 of another gene, called PIKFYVE.

MPseq is a next-generation whole-genome sequencing-based technology. It is specifically optimized to detect structural chromosome changes such as deletions, duplications, translocations, and inversions. It uses long-insert paired-end reads and, therefore, provides greater bridged coverage of the genome. This means that the whole genome can be assessed at a reduced cost.

The same technique also identified the same germ-line chromosomal inversion disrupting the BMRP2 gene in the patient’s sister and her maternal cousin. 

“(…) MPseq could be considered for all patients in which standard genetic techniques failed to identify a pathogenic variant”, the researchers concluded. 


Chalmers SJ, Murphy SJ, Thompson LL, et al. Mate-pair sequencing identifies a cryptic BMPR2 mutation in hereditary pulmonary arterial hypertension. Pulm Circ. Published online July 12, 2021. doi:10.1177/2045894020933081