An Ancient Founder GDF2 Variant Potentially Causes Semi-Dominant Non-Syndromic Pulmonary Arterial Hypertension

Growth differentiation factor 2 (GDF2), also known as bone morphogenetic protein-9 (BMP9), is a key member of the transforming growth factor-beta (TGF-β) superfamily, playing a pivotal role in pulmonary vascular regulation and remodeling. Dominant variants in GDF2 are known to cause hereditary hemorrhagic telangiectasia type 5 (HHT5), a condition characterized by telangiectases and arteriovenous malformations (AVMs). More recently, recessive variants in GDF2 have been reported to cause pulmonary arterial hypertension (PAH) with or without features of HHT5. In this study, we identified a founder variant in GDF2 that potentially causes semidominant PAH in a cohort of 13 patients ranging in age from pediatric to middle-aged adults. Careful clinical evaluation revealed a wide range of ages of onset and disease severity. However, lack of HHT manifestations was a consistent clinical feature. Our results lend further support to GDF2 as a bona fide disease gene in the context of non-syndromic PAH and demonstrate the power of founder variants to reveal the full spectrum of disease variability.