Sofia Karl, Ekkehard Grünig, Memoona Shaukat, Matthias Held, Christian Apitz, Fabian von Scheidt, Ralf Geiger, Michael Halank, Karen M. Olsson, Marius M. Hoeper, Jan C. Kamp, Gabor Kovacs, Horst Olschewski, Hans-Jürgen Seyfarth, Katrin Milger, Ralf Ewert, Hans Klose, Benjamin Egenlauf, Panagiota Xanthouli, Katrin Hinderhofer, Christina A. Eichstaedt
Heidelberg University Hospital and Heidelberg University. KWM Missio Clinic. University Hospital Ulm. German Heart Center Munich. Medical University Innsbruck. University Hospital Carl Gustav Carus of TU Dresden. Hannover Medical School. Medical University of Graz. University Hospital of Leipzig. Ludwig-Maximilian University of Munich. University of Greifswald. University Medical Center Hamburg-Eppendorf.
Germany and Austria
Nature Partner Journals Genomic Medicine
NPJ Genom Med 2025; 10:
DOI: 10.1038/s41525-025-00484-6
Abstract
In patients with complex congenital heart disease (CHD) pathogenic SMAD6 variants have been described previously. The aim of this study was to analyze if pathogenic SMAD6 variants also occur in patients with CHD associated with pulmonary arterial hypertension (CHD-APAH) or idiopathic PAH. A PAH gene panel with up to 64 genes including SMAD6 was used to sequence 311 patients with idiopathic PAH (IPAH) and 32 with CHD-APAH. In 4 of 32 (12.5%) CHD-APAH and in 2 out of 311 (0.64%) IPAH patients we identified likely pathogenic or rare SMAD6 missense variants. All CHD-APAH patients with a rare SMAD6 variant had complex CHD. One patient had bi-allelic SMAD6 variants, combined pulmonary valve defect and supravalvular aortic stenosis, craniosynostosis and radioulnar synostosis. This is the first description of potentially disease-causing SMAD6 variants in patients with IPAH and complex CHD-APAH. Further studies are needed to assess pathogenesis and prevalence of pathogenic SMAD6 variants in PAH.
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes