1Thoraxklinik - Heidelberg gGmbH Pneumologie und Beatmungsmedizin / Zentrum für Pulmonale Hypertonie Heidelberg, Deutschland; 2Missionsärztliche Klinik Würzburg Innere Abteilung Würzburg, Deutschland; 3Bundeswehrkrankenhaus Ulm Innere Medizin - Kardiologie Ulm, Deutschland; 4Deutsches Herzzentrum München München, Deutschland; 5Institut für Humangenetik Heidelberg, Deutschland
Background: PAH can be caused by genetic predispositions. The TGF-β pathway gene BMPR2 has the highest prevalence in (likely) pathogenic variants, but further genes have been described being responsible for the pathogenesis of PAH and other forms such as congenital heart disease associated PAH (CHD-APAH).
Objective: The aim of the study was to identify further causative genes and variants for patients with CHD-APAH.
Methods: A PAH gene panel, with 18 diagnostic and up to 46 candidate genes, was used to sequence 27 CHD-APAH patients which have been diagnosed according to the guidelines including right heart catheterization. Variants were characterized according to ACMG criteria.
Results: Two out of 27 patients with CHD-APAH presented with a heterozygous frameshift variant in the TGF-β pathway gene SMAD6. SMAD6 is one of two inhibitory SMAD proteins regulating TGF-β-signaling including BMPR2-signalling. The first variant c.590_602del p.(S197Cfs*41) was a deletion of 13 basepairs in exon 1 of 4 exons in the SMAD6 gene leading to a frameshift and a premature stop codon. The patient was diagnosed with PAH in infancy and had a mild valvular and supravalvular aortic stenosis, craniosynostosis and radioulnar synostosis. The second PAH patient revealed a SMAD6 gene variant c.592dup p.(Arg198Profs*105) as single base pair duplication in exon 1 leading to a frameshift and premature stop codon. The CHD-APAH patient was born with an agenesis of the right pulmonary artery, bicuspid aortic valve and an aneurysm of the ascending aorta. Since both variants were absent in 60,000 healthy controls (gnomAD v2.1.1) and loss of function is a known mechanism of disease in SMAD6, these variants can be classified as likely pathogenic. This study is the first description of SMAD6 mutations in patients with PAH.
Conclusion: The results of this study suggest that the identified SMAD6 mutations are causative for CHD-APAH or syndromic form of PAH with CHD, respectively. Further studies in this patient cohort are needed to confirm these findings and to assess the incidence of disease causing SMAD6 mutations.