Multiple mutations signal poor PAH outcomes
medwireNews: Patients with multiple mutations in genes linked to pulmonary artery hypertension (PAH) have severe disease and a poor response to treatment, report researchers.
Diana Valverde (University of Vigo, Spain) and colleagues screened 57 unrelated Caucasian PAH patients for mutations in the PAH-linked genes BMPR2, ACVRL1, ENG and KCNA5, finding at least one mutation with a predicted pathogenic effect in 72% of the patients.
The most commonly affected gene was BMPR2, which was mutated in 44% of patients, “reinforcing the role of this gene in the development of PAH”, say the researchers. Following this was ENG, which was mutated in 29%, and ACVRL1, mutated in 17%, while KCNA5 was mutated in 10%.
Fifteen of the patients with pathogenic mutations had more than one, with some having single mutations in more than one gene, but others having more than one mutation in the same gene.
“We cannot rule out that patients with a single pathogenic mutation have other mutations in genes not included in this study”, write the researchers in Scientific Reports. “There is no doubt that other genes could be involved in PAH and it will be important to understand their role in the development of the disease.”
Patients with several pathogenic mutations were more likely than those with just one to be female, and seemed to have more severe disease and worse outcomes. They developed PAH symptoms at an average of 11 years younger than patients with just one mutation, had significantly higher pulmonary vascular resistance and lower cardiac output, and a reduced likelihood of responding to treatment. The findings were similar when comparing patients with multiple pathogenic mutations with those who had none.
Valverde and team speculate that “these additional mutations act as a second event in the development of the disease, increasing the penetrance or simply modifying the phenotype of patients.”
They suggest that PAH patients with multiple mutations may need highly specific treatment, “in some cases directed to more than one cellular pathway.”
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