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

Approximately 25%-30% of patients diagnosed with idiopathic pulmonary arterial hypertension (PAH) have a clustered underlying Mendelian genetic cause and should be classified as heritable PAH (HPAH). The sixth World Symposium on Pulmonary Hypertension listed AQP1 as a PAH-related gene. AQP1 and its protein product Aquaporin-1 (AQP1) are found in abundance within pulmonary artery smooth muscle cells. Here, we report a family affected by HPAH with all three siblings carrying the same novel missense variant of AQP1 c.273C>G (p.Ile91Met). The youngest brother and the older sister both had dyspnea and edema and were diagnosed with HPAH about 10 years ago. In 2021, they received genetic tests that revealed all three siblings carried the same novel variant of AQP1 (c.273C>G). The brother in between these two siblings, although originally claimed to be asymptomatic, raised awareness. He then sought medical examination and confirmed the diagnosis of HPAH as well. This report on all three siblings carrying the same novel variant of AQP1 (c.273C>G) highlighted the importance of genetic testing and counseling for family members when PAH was first detected.