Genetic Landscape of PAH Differs Between Children and Adults, Study Shows

Alice Melão, MSc avatar

by Alice Melão, MSc |

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genetic variants, PAH

The genetic landscape of pulmonary arterial hypertension that strikes in childhood differs from the one that develops after a person reaches adulthood, a study reports.

There is little variation between children and adults in gene mutations commonly associated with PAH, such as BMPR2. But children have more of the rarer mutations, like TBX4, researchers reported.

Their study, “Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults,” appeared in the journal Circulation: Genomic and Precision Medicine.

Scientists have identified several genes that increase the risk of a person developing PAH. While mutations have been studied in adult-onset PAH, little has been known about mutations that cause cases in children.

A research team decided to remedy this. Their study included 155 children and 257 adults with PAH who had been treated at Columbia University over 22 years.

Participants were grouped according to how their disease originated. One group consisted of patients with the inherited form — familial, or FPAH. The other consisted of those with the non-genetic form — idiopathic, or IPAH.

Researchers screened FPAH patients for variations of the BMPR2 and ACVRL1 genes associated with the disease.

They then used an advanced genetic screening method called exome sequencing on all of the IPAH patients and on the FPAH patients with no BMPR2 or ACVRL1 mutation. The goal was to find mutations that had not been identified before.

A key finding was a similar frequency of BMPR2 mutations between those who developed PAH as children and those who developed it as adults, regardless of whether they had familial or idiopathic PAH.

The figures were 56 percent of those who developed FPAH as children, versus 54 percent of those who developed it as adults. The figures in IPAH were 10 percent and 8 percent.

But the types of mutations in children were different from those in the adult-onset group.

Sixty-three of the FPAH patients had BMPR2 or ACVRL1 mutations. Eighty-four of the  IPAH patients had rare variations of BMPR2, including 14 that researchers had just identified.

The team also discovered 13 never-before-identified mutations of TBX4 gene. Twelve were in children and one in an adult-onset patient, suggesting that these mutations are much more frequent in children.

Researchers also analyzed the genetics of the children’s parents. This confirmed that the children had inherited their TBX4 mutations.

Another discovery was 12 rare mutations in genes previously linked to PAH. These included abnormalities of the KCNK3, CAV1, EIF2AK4, ENG, SMAD9, and BMPR1B genes. The frequency of these mutations was similar between the children and adult-onset patients — 5.8 percent versus 5.1 percent.

Taken together, the findings demonstrated that mutations of BMPR2 or other genes that play a role in the TGF-beta signaling pathway accounted for about 55 percent of FPAH cases in both children and adults.

In addition, newly discovered mutations accounted for about 19 percent of IPAH cases in children. Children also had more TBX4 mutations.

The newly discovered mutations accounted for “a significant fraction of PAH in children,” the researchers wrote. They also suggested an important strategy — exome sequencing — for identifying additional mutations.

“The genetic assessment of larger pediatric study cohorts could provide an important opportunity to identify novel genes [associated with PAH], elucidate the mechanisms of PAH, and provide targets for future therapies,” the team said.