Pathogenic SMAD6 variants in patients with idiopathic and complex congenital heart disease associated pulmonary arterial hypertension
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.
Authors
- Jan C. Kamp (ORCID: https://orcid.org/0000-0002-5002-409X)
- Ralf Ewert (ORCID: https://orcid.org/0000-0002-6746-9925)
- Marius M. Hoeper (ORCID: https://orcid.org/0000-0001-9086-2293)
- Panagiota Xanthouli (ORCID: https://orcid.org/0000-0002-7743-2472)
- Katrin Milger (ORCID: https://orcid.org/0000-0003-2914-8773)
- Christina A. Eichstaedt (ORCID: https://orcid.org/0000-0001-7288-8297)
- Michael Halank (ORCID: https://orcid.org/0000-0002-9184-4799)
- Ralf Geiger (ORCID: https://orcid.org/0000-0003-3689-1207)
- Christian Apitz (ORCID: https://orcid.org/0000-0002-6780-8077)
- Memoona Shaukat (ORCID: https://orcid.org/0000-0002-1222-0911)
- Fabian von Scheidt (ORCID: https://orcid.org/0000-0002-3431-0862)
- Matthias Held (ORCID: https://orcid.org/0000-0002-5855-7667)
- Hans F. E. Klose (ORCID: https://orcid.org/0000-0002-7215-0943)
- Horst Olschewski (ORCID: https://orcid.org/0000-0002-2834-7466)
- Ekkehard Grünig (ORCID: https://orcid.org/0000-0001-7318-3918)
- Benjamin Egenlauf (ORCID: https://orcid.org/0000-0003-2466-1420)
- Katrin Hinderhofer (ORCID: https://orcid.org/0000-0003-1493-4608)
- Gábor Kovács (ORCID: https://orcid.org/0000-0003-3709-2183)
- S. R. Karl
- Karen M. Olsson
- Hans-Jürgen Seyfarth
Institutions
- Innsbruck Medical University (AT)
- Universität Hamburg (DE)
- Medical University of Graz (AT)
- Heidelberg University (DE)
- Universitätsmedizin Greifswald (DE)
- University Hospital Heidelberg (DE)
- Medizinische Hochschule Hannover (DE)
- Universität Greifswald (DE)
- Ludwig Boltzmann Institute for Lung Vascular Research (AT)
- University Medical Center Hamburg-Eppendorf (DE)
- Institute of Human Genetics (PL)
- Asklepios Fachkliniken München-Gauting (DE)
- University Hospital Leipzig (DE)
- German Center for Lung Research (DE)
- Klinikum Würzburg Mitte (DE)
- Deutsches Herzzentrum München (DE)
- University Hospital Ulm (DE)
- University Hospital Carl Gustav Carus (DE)
- Technische Universität Dresden (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1038/s41525-025-00484-6
- Citations
- 3
- Primary Topic
- Pulmonary Hypertension Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.56