New IPAH Gene Variants Identified in Large Global Study

A study of rare gene variants has identified two new candidates — fibulin 2 (FBLN2) and platelet-derived growth factor D (PDGFD) — that increase risk for adult-onset idiopathic pulmonary arterial hypertension (IPAH).

In-depth genetic analyses also predicted that about 15% of IPAH cases in children are caused by de novo variants, which means they are not inherited from the parents.

The study, “Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH,” was published in Genome Medicine.

PAH usually arises in people with no known family history of the condition. Mutations in a gene linked to PAH, called BMPR2, have been found in up to 20% of cases previously classified as idiopathic, meaning with no identified cause, but disease-causing mutations remain unidentified in a relevant percentage of patients.

When PAH is inherited, also known as familial (FPAH), it typically follows an autosomal dominant pattern of inheritance where one copy of an altered gene is enough to cause disease. However, many people with one copy never develop the condition. This suggests the presence of other contributing factors that may be genetic and/or environmental.

Previous studies have indicated that rare genetic mutations are estimated to be the cause of about 75%–80% of FPAH, at least 10% of adult-onset IPAH, and up to about 36% of pediatric-onset IPAH. As such, many non-familial PAH cases remain genetically undefined.

To address this knowledge gap, researchers in the U.S. and U.K. set out to determine risk variants for several genetic subtypes of PAH.

The analysis was carried out in a total of 4,241 PAH cases from the National Biological Sample and Data Repository for PAH, U.K. NIHR BioResource — Rare Diseases Study, and Columbia University Irving Medical Center.

The analysis of de novo variants included a subset of 124 trios of affected children but unaffected parents.

The combined U.S./U.K. group included 54.6% IPAH, 34.8% APAH, 5.9% FPAH, and 4.6% other types of pulmonary arterial hypertension. APAH refers to PAH associated with connective tissue diseases, congenital heart disease, and others.

Most of the cases were adult-onset (92.6%) and the mean age at diagnosis was 45.9 years. The majority of patients were female (75.1%) and European (74.5%). Other ethnicities included African (8.7%), Hispanic (8.6%), South Asian (2.8%), and East Asian (2.5%).

Among pediatric-onset cases, the female-to-male ratio was significantly lower compared to the adult-onset cases.

Rare variants in the gene BMPR2 that increase PAH risk were identified in 7.7% of overall cases (9% of IPAH, 56.6% of FPAH, and 0.88% of APAH). Previous studies have identified more than 600 BMPR2 gene variants that cause FPAH.

When limiting their search to European cases, the researchers found rare predicted variants in seven genes — BMPR2, GDF2, TBX4, SOX17, KDR, FBLN2, and PDGFD — that were significantly associated with IPAH.

FBLN2 and PDGFD have known functions in blood vessel formation and remodeling. Both genes showed missense variants, which means a change in the genetic sequence that leads to the production of a different amino acid — the building blocks of proteins.

Next, the entire combined group was screened, including patients of non-European ancestry, for rare missense variants in FBLN2 and PDGFD. Seven cases were found to carry FBLN2 mutations (six IPAH and one APAH) and 10 cases carried PDGFD variants — nine IPAH and one PAH. Most of the carriers were of European ancestry.

FBLN2 mutation carriers had increased mean pulmonary capillary wedge pressure, a measure of pressure on the left side of heart, compared to the overall group. All the FBLN2 and PDGFD variant carriers were diagnosed with PAH class II or III, and five out of seven FBLN2 carriers had systemic (body-wide) hypertension.

The team then analyzed the subset of 124 child-parent trios and found that it consisted of 55.6% IPAH cases and 37.9% APAH-congenital heart disease cases. Seven of the variants were found in known PAH risk genes: four in TBX4, two in BMPR2, and one in ACVRL1.

Among the IPAH cases, the variants were missense or classified as likely gene-disrupting and missense. In addition, the trio analysis predicted that about 15% of pediatric IPAH could be explained by de novo variants.

The rare de novo variants carried by PAH cases in children were linked to genes implicated in several developmental syndromes, such as Noonan syndrome. In the patients who carried likely gene-disrupting or missense de novo variants, the team found a higher ratio of girls vs. boys with a mean age of onset of 5.4 years. The researchers found that 50% of the cases had IPAH, 33.3% APAH-congenital heart disease, and an overlap of 36.1% of cases had other congenital or growth and development conditions.

“We have identified FBLN2 and PDGFD as new candidate risk genes for adult-onset IPAH,” the scientists wrote. “We estimate that [approximately] 15% of all pediatric cases are attributable to de novo variants and that many of these genes are likely to have important roles in developmental processes. Larger adult and pediatric [groups] are needed to better clinically characterize these rare genetic subtypes of PAH.”