Pathogenic Glomulin Gene Variant in a Patient with Idiopathic Pulmonary Arterial Hypertension: A Novel Association Case Report

Abstract

Background and Clinical Significance: Idiopathic pulmonary arterial hypertension is a rare disorder, often linked to genetic predisposition. Canonical pulmonary arterial hypertension genes such as BMPR2, KCNK3, and TBX4 are well described, but novel associations continue to emerge. Glomulin (GLMN) encodes a protein essential for vascular smooth-muscle biology, classically implicated in glomuvenous malformations, yet not previously associated with pulmonary arterial hypertension. Case Presentation: We present a 49-year-old woman with progressive dyspnea, edema, and persistent hypercapnic respiratory failure. Right-heart catheterization confirmed precapillary pulmonary hypertension. Comprehensive evaluation, including ventilation/perfusion scanning, autoimmune panel, polysomnography, and high-resolution computed tomography, excluded secondary causes. Respiratory assessment revealed diaphragmatic weakness and reduced respiratory muscle pressures, consistent with primary myopathy and explaining the unusual hypercapnic profile. Whole-genome sequencing identified a heterozygous pathogenic GLMN nonsense variant, while canonical pulmonary arterial hypertension genes were negative. No cutaneous or mucosal glomuvenous malformations were found. The patient was treated with oxygen therapy, diuretics, non-invasive ventilation, and dual oral pulmonary arterial hypertension therapy (ambrisentan and tadalafil), with stabilization but persistent hypercapnia. Conclusions: To our knowledge, this is the first reported co-occurrence of idiopathic pulmonary arterial hypertension and a pathogenic GLMN variant. While causality cannot be inferred, glomulin's role in vascular smooth-muscle maturation provides a plausible link to pulmonary vascular remodeling. This case underscores the importance of assessing respiratory muscle function in idiopathic pulmonary arterial hypertension patients with hypercapnia and highlights the potential relevance of extended genetic testing in rare pulmonary vascular disease.

Keywords: case report; glomulin (GLMN) gene; pulmonary arterial hypertension; respiratory muscle weakness; vascular smooth muscle; whole-genome sequencing.