Study Identifies New Gene Mutations Associated with Heritable PAH

A Japanese study of nine families members who have heritable pulmonary arterial hypertension (HPAH) found different mutations in the same gene, called BMPR2, four of which had been identified before and four newly identified. Researchers also found a new mutation in another gene, KCNK3, that caused HPAH in another family.

The researchers believe that the findings can contribute to the development of a genetic test for HPAH.

The study, “A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension,” was published in the journal BMC Pulmonary Medicine.

Pulmonary arterial hypertension (PAH) is caused by increased blood pressure in the arteries supplying blood to the lungs, and can ultimately result in death due to heart failure.

In total, the study included nine families — 17 family members — and compared mutations in the genomes of the family members to 300 reference genomes from healthy individuals.

The study used a new method called genome-wide association analysis, in which the complete DNA (the genome) from each individual is sequenced to detect abnormal changes called mutations.

Gene mutations are the cause of heritable diseases, but in the case of HPAH it is not so simple, as a person may have the gene mutation, but does not necessarily develop the disease. Such mutations in heritable diseases have what is called “low penetrance,” when few of the mutation carriers develop the disease.

In genome-wide association analysis, when a high number of people with a specific disease are found to have a mutation in a particular gene compared to people without the disease, the mutation is said to be associated with the disease — to be a likely cause of it.

Researchers have now found eight different mutations in a single gene, BMPR2, and one mutation in another gene, KCNK3, which were associated with HPAH. Mutations in KCNK3 have not been previously observed in association with HPAH.

“To our knowledge, this is the first report of gene-based genome-wide association analysis of HPAH. A burden of rare variants in BMPR2 significantly contributes to risk of the disease,” the research team wrote. “The variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing.”

The team suggests that sequencing candidate genes is important to further understand the genetic factors linked to PAH.