Case Report of Novel Variant in Patient With PAH Highlights Benefit of Genetic Testing

Findings from a case report are highlighting the utility of genetic testing for pulmonary arterial hypertension (PAH).

The case, coming from a center in Taiwan that care for patients with PAH, shares the details of a young woman with heritable PAH and a novel heterozygous missense variant. Subsequent testing revealed the presence of the variant in both of her siblings, also underscoring the importance of counseling family members with the condition.

The investigators published their findings in Pulmonary Circulation.

The novel heterozygous missense variant was first identified in a 36-year-old woman presenting to the researchers’ PAH clinic. The patient, presenting with dyspnea and edema, had right ventricular hypertrophy and dilated right atrium and right ventricle. Mean pulmonary arterial pressure was 57 mm Hg and pulmonary vascular resistance was 20 Wood units.

Enrollment in a clinical trial revealed the missense variant of AQP1 c.273C>G (p.Ile91Met).

“Regarding the pathogenic potential of AQP1 c.273C>G (p.Ile91Met), it was a novel variant and has not been previously reported in the ClinVar database. Therefore, we evaluated this variant following the recommendations of the 2015 American College of Medical Genetics (ACMG) guideline,” explained the researchers, noting that the variant was deemed as “likely pathogenic,” meeting 1 moderate and 4 supporting criteria for PAH.

APQ1 has been identified by the 6th World Symposium on Pulmonary Hypertension as a gene related to PAH, and to date, 12 variant sires in AQP1 have been documented across 12 cases of PAH, including those that were missense, one nonsense, and one frameshift.

Following her genetic results, the patient’s 2 siblings received genetic testing, revealing they both carried the same variant site. One brother was the proband of PAH while the other was seemingly asymptomatic; however, after receiving his genetic results, sought examination and received a confirmed diagnosis of PAH.

The researchers noted that they were unable to identify further information on the inheritance mode of the variant, as the parents of the 3 siblings declined genetic testing. To date, they show no symptoms of PAH. The group also wrote that there are no available in vitro studies showing that the variant can alter the function of AQP1, resulting in the development of PAH.

“Regarding the impact of AQP1 gene variants on PAH survival, reported cases were still limited and there was no survival analysis yet,” described the researchers. “However, the meta-analysis reported that PAH subjects who carried the BMPR2 genetic variants had worse survival than noncarriers. Similarly, the PAH subjects with ACVRL1 genetic variant had worse survival than non-carriers. Therefore, it is intuitive that all 3 siblings should be closely followed to observe disease progression.”

Reference

Liang KW, Chang SK, Chen YW, Tsai WJ, Wang KY. A cluster of heritable pulmonary arterial hypertension cases in a family with all three siblings carrying the same novel AQP1 c.273C>G variant‐a case report. Pulm Circ. Published online March 21, 2023. doi:10.1002/pul2.12211