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. 2025 Mar 25;10(1):28.
doi: 10.1038/s41525-025-00484-6.

Pathogenic SMAD6 variants in patients with idiopathic and complex congenital heart disease associated pulmonary arterial hypertension

Sofia Karl  1   2 , Ekkehard Grünig  1 , Memoona Shaukat  1   2 , Matthias Held  3 , Christian Apitz  4 , Fabian von Scheidt  5 , Ralf Geiger  6 , Michael Halank  7 , Karen M Olsson  8 , Marius M Hoeper  8 , Jan C Kamp  8 , Gabor Kovacs  9 , Horst Olschewski  9 , Hans-Jürgen Seyfarth  10 , Katrin Milger  11 , Ralf Ewert  12 , Hans Klose  13 , Benjamin Egenlauf  1 , Panagiota Xanthouli  1   14 , Katrin Hinderhofer  2 , Christina A Eichstaedt  15   16
Affiliations

Pathogenic SMAD6 variants in patients with idiopathic and complex congenital heart disease associated pulmonary arterial hypertension

Sofia Karl et al. NPJ Genom Med. .

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.

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Conflict of interest statement

Competing interests: E.G., K.H., and CA.E. are the inventors of the issued European patent “Gene panel specific for pulmonary hypertension and its uses” (EP3507380). The patent applicants are the Thoraxklinik-Heidelberg gGmbH and the Ruprecht-Karls-Universität Heidelberg. The panel was used for the NGS sequencing of all patients in this study. E.G. received fees for lectures and/or consultations from Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. C.A.E. received honoraria for lectures and presentations from OMT and MSD, consulting fees from MSD outside the submitted work. M.a.H. received consulting frees from Bayer Healthcare, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, MSD, Pfizer; honoraria for lectures from: AstraZeneca, Bayer HealthCare, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Daichi Sankyo, Janssen, MSD, Pfizer, Santis outside the submitted work. CA received honoraria from Janssen outside the submitted work. M.i.H. received honoraria for lectures and/or consulting from AstraZeneca, Janssen und MSD outside the submitted work. K.M.O. served as consultant or speaker for Acceleron Pharma, Inc., Actelion Pharmaceuticals, AOP Orphan, Bayer Healthcare, Ferrer, GossamerBio, Janssen Global Services, LLC, and Merck & Co., Inc. (Rahway, NJ, USA) (paid to self) outside the submitted work. M.M.H. served as consultant or speaker for Acceleron Pharma, Inc., Actelion Pharmaceuticals, AOP Orphan, Bayer Healthcare, Ferrer, GossamerBio, Janssen Global Services, LLC, and Merck & Co., Inc. (Rahway, NJ, USA) (paid to self) outside the submitted work. G.K. received honoraria for lectures and/or consulting from Janssen, Boehringer-Ingelheim, AstraZeneca, Bayer, MSD, Chiesi, Ferrer, AOP outside the submitted work. H.O. received honoraria for lectures and/or consulting from AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Iqvia, Janssen, MedUpdate, Menarini, MSD, Novartis and Pfizer outside the submitted work. H.J.S. received honoraria for lectures and/or presentations from Janssen-Cilag and Ferrer outside the submitted work. K.M. received honoraria for lectures and/or consulting from AOP, AstraZeneca, Chiesi, GSK, Janssen, MSD, Novartis, Sanofi outside the submitted work. R.E. received honoraria fees for consulting and/or lectures from AstraZeneca, AOP Orphan, Bayer, Berlin Chemie, GSK, Janssen Pharmaceutical Companies of Johnson & Johnson, LungPacer, Novartis, Merc, OMT and Pfizer, and research support from OMT and Boehringer Ingelheim outside the submitted work. H.K. received honoraria for lectures and/or consulting Bayer, Gossamer Bio, Janssen Cilag, MSD, Orphacare und Pfizer, OMT, United Therapeutics outside the submitted work. B.E. received travel fees, consulting fees, speaking fees, and/or honoraria from Actelion, MSD, Bayer and OMT, outside the submitted work. P.X. received speaker fees from Janssen, MSD and OMT outside the submitted work. F.v.S., J.C.K., K.H., M.S., R.G., S.K.: nothing to declare.

Figures

Fig. 1
Fig. 1. Flow diagram of the two study cohorts.
Of the 343 included patients, 32 were diagnosed with congenital heart disease associated pulmonary arterial hypertension (CHD-APAH) and 311 with idiopathic PAH (IPAH). Of the latter 65 had cardiopulmonary comorbidities and in total 31 were re-classified to heritable PAH (HPAH). The majority of congenital heart defects was discovered prior to PAH diagnosis.
Fig. 2
Fig. 2. Central illustration with described phenotypes and roles for SMAD6 and SMAD6 variants identified in this study.
Pathogenic SMAD6 variants have been previously described to cause radioulnar synostosis, heart defects and craniosynostosis. Heart defects result from disrupted embryonic cardiovascular development. This study identified 4 missense and 3 frameshift variants in 4 congenital heart disease associated pulmonary arterial hypertension (CHD-APAH) and 2 idiopathic PAH patients. Bold variants were classified as likely pathogenic. Created with BioRender.com.
Fig. 3
Fig. 3. Pedigree of the second patient’s family with 2 SMAD6 variants.
The index patient was diagnosed at the age of 7 months and is now aged 28 years. He carried two biallelic SMAD6 variants c.590_602del p.(Ser197Cysfs*41) and c.787C>T p.(Pro263Ser). Each variant was inherited from one parent. Circles denote females, squares males, strike through deceased individuals and filled symbols the presence pulmonary arterial hypertension.
See this image and copyright information in PMC

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