BMPR2 Splice-Site Variant in a Patient With Pulmonary Arteriovenous Malformation and Delayed-Onset Pulmonary Arterial Hypertension: A Case Report and Mechanistic Phenocopy Hypothesis

Akshay Mathavan; Akash Mathavan; Urszula Krekora; Olga Romina Gomez Rojas; Khanh Huynh; Mason Lin; Judy Dinh; Marc S Zumberg; Jeb Justice; Ali Ataya

doi:10.1002/ajmg.a.70109

BMPR2 Splice-Site Variant in a Patient With Pulmonary Arteriovenous Malformation and Delayed-Onset Pulmonary Arterial Hypertension: A Case Report and Mechanistic Phenocopy Hypothesis

Am J Med Genet A. 2026 Mar 8. doi: 10.1002/ajmg.a.70109. Online ahead of print.

Authors

Affiliations

¹ Department of Internal Medicine, University of Florida, Gainesville, Florida, USA.
² College of Medicine, University of Florida, Gainesville, Florida, USA.
³ Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, Florida, USA.
⁴ Division of Hematology/Oncology, University of Florida, Gainesville, Florida, USA.
⁵ Department of Otolaryngology Head and Neck Surgery, University of Florida, Gainesville, Florida, USA.

PMID: 41795626
DOI: 10.1002/ajmg.a.70109

Abstract

Pulmonary arteriovenous malformations (PAVMs) are rare vascular anomalies most commonly seen in hereditary hemorrhagic telangiectasia (HHT), a condition associated with mutations in ENG, ACVRL1, SMAD4, or GDF2. In contrast, BMPR2 variants are well-established in heritable pulmonary arterial hypertension (PAH), but their relationship to PAVMs remains poorly understood. We report the case of a 41-year-old woman with an incidentally discovered PAVM, initially treated with embolization and subsequent surgical resection. She remained asymptomatic for several years until progressive exertional dyspnea led to a diagnosis of severe precapillary PAH. Genetic testing identified a heterozygous BMPR2 splice-site variant (c.967 + 5G>A), previously reported in a PAH cohort but currently classified as a variant of uncertain significance. This report is notable for the delayed evolution from isolated PAVM to PAH in the context of a BMPR2 variant, raising the possibility of a mechanistic link outside the canonical HHT pathway. We review published reports of BMPR2-associated PAVMs, some of which include subtle HHT-like features, such as mucocutaneous telangiectases and epistaxis, despite negative testing for classical HHT genes. These observations suggest a potential phenocopy vascular syndrome driven by disruption of the shared bone morphogenetic protein 9 (BMP9)-ALK1 signaling axis. We also discuss the implications of sotatercept, a transforming growth factor-beta (TGF-β) superfamily ligand trap, which in this case was associated with symptomatic improvement and stable shunt burden. These findings contribute to the emerging recognition of atypical vascular phenotypes in BMPR2 variant carriers, particularly those presenting with PAVMs in the absence of HHT. It highlights the importance of considering genetic testing in isolated AVM presentations, as well as the need for longitudinal surveillance and mechanistic investigation into overlapping TGF-β/BMP signaling disorders.

Keywords: TGF‐β superfamily; bone morphogenetic protein signaling; hereditary hemorrhagic telangiectasia phenocopy; heritable pulmonary arterial hypertension; intrapulmonary shunting; pulmonary arteriovenous malformation; sotatercept; splice site variant.

Publication types

Case Reports