Rare GDF2 Mutation Linked to Idiopathic PAH in Brother and Sister

Family's case raises to five known number of pediatric PAH due to this mutation

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration of four children, including one in a wheelchair, holding hands.

A rare mutation in the GDF2 gene was identified in two siblings, a boy and a girl, with pulmonary arterial hypertension (PAH), according to a recent case report.

The mutation, which each child inherited in both gene copies, resulted in a lack of the bone morphogenetic protein (BMP) 9 in the blood and low levels of a related protein, called BMP10.

Their parents, who each had one copy of the mutation, have no signs of the disease or other health concerns, but their BMP9 and BMP10 levels were low relative to healthy adults matched by sex.

The report, “A rare homozygous missense GDF2 (BMP9) mutation causing PAH in siblings: Does BMP10 status contribute?,” was published in the American Journal of Medical Genetics Part A.

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The growth differentiation factor 2GDF2 — gene belongs to a group of genes responsible for producing BMPs, a family of growth factors important for maintaining tissue architecture throughout the body.

Mutations in GDF2, which encodes for BMP9, are known to cause PAH in adults and children, but only three cases have been described in pediatric patients to date, according to the research team in Canada and the U.K.

In this report, the researchers described two additional cases — a brother and sister diagnosed with idiopathic PAH (PAH with no known cause) in whom a GDF2 mutation was identified through genetic testing.

The boy, age 11, had been diagnosed with IPAH at 3 months old, and his sister, age 8, was diagnosed when she was 4 years old.

According to the World Health Organization criteria, the boy had a Class 2 functional status, indicating no PAH symptoms at rest but shortness of breath with exercise. The girl’s classification is 1–2, with intermittent shortness of breath during exercise. Overall, the boy was seen to have somewhat more severe PAH, the team noted.

Blood samples collected from the children and their parents underwent genetic sequencing for 14 genes in which mutations are known to cause PAH.

Both children had inherited two mutated copies of the GDF2 gene, one from each parent, making them homozygous for the mutation, results showed. The mother and father, each with one affected gene copy, were heterozygous for the mutation.

The researchers noted that this same mutation, called c.958A > T, has been identified in adult PAH patients, but the siblings mark the first reported pediatric cases. The identified adults have been heterozygous for the mutation.

For BMP9 to reach its fully functional form, a precursor domain and the functional growth factor domain of the gene must be cleaved apart. The mutation lies between the two domains, where it disrupts BMP9 processing.

Notably, BMP9 protein could not be detected in the blood of either child and was low in both parents.

Levels of the related BMP10 protein were low for both the children and their parents relative to samples from healthy individuals.

In the girl, the ratio of BMP10’s growth factor domain — the functional part — to the precursor domain was higher than for the other family members, suggesting a greater availability of functional BMP10.

“We speculate that the earlier disease onset and greater severity in the male … child may be a consequence of BMP9 loss combined with low BMP10, whereas the impact of BMP9 loss in his sister may be mitigated by residual circulating BMP10,” the researchers wrote.

BMP activity was detectable in the blood, which could reflect BMP10, and not BMP9, activity, they noted.

The scientists suggested that while GDF2 mutations might predispose a person to PAH, other factors are needed to drive the disease. That could explain why the children’s parents, who also each had a GDF2 mutation and low BMP9 levels, had no signs of PAH.

“Unaffected heterozygous individuals with reduced BMP9 levels suggest that heterozygous deleterious GDF2 variants predispose to disease but are not sufficiently causal,” the researchers wrote.

A Conversation With Rare Disease Advocates