New phenotypic association for SMAD6 gene: its role in the development of cardiac conduction disorders and pulmonary arterial hypertension/hereditary haemorrhagic telangiectasia

Abstract Introduction Pathogenic variants in the SMAD6 gene have been associated with the development of different congenital malformations. From the cardiac point of view, its involvement in congenital disorders (CHD) of the outflow tract and conotruncal defects has been described. The underlying mechanism appears to be loss of function in an autosomal dominant manner. Meta-analyses performed on whole-genome-sequencing have suggested the association of SMAD6 with cardiac conduction disorders (CCD); on the other hand, SMAD6 is a candidate gene for pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT) because it is involved in the BMP/ENG signalling pathway. However, SMAD6 truncating variants (SMAD6tv) appear in general population databases, and no case-control studies have been performed; therefore the association of the gene with these phenotypes has not yet been demonstrated. Purpose This study sought to investigate the relationship between SMAD6tv and the development of CCD and/or PAH/HHT. Methods SMAD6 was sequenced by next-generation-sequencing in almost 18,000 unrelated probands studied for suspected inherited heart diseases. Probands with a CCD, CHD, PAH or HHT diagnosis were considered cases. Probands with cardiomyopathies were considered internal controls. In addition, we used data extracted from the gnomAD database (v4. 1) as external controls. An enrichment and cosegregation study of SMAD6tv was performed, and clinical features in carriers were analyzed. Results We identified 18 probands harbouring 17 SMAD6tv among cases. Variant frequencies were significantly higher in cases (18/1,130; 1.6%) than in internal (10/8,552, 0.1%) and external controls (815/727,053; 0.1%), with an OR of 13.8 (CI95%: 9.0-23.1; p0.0001) and 14.4 (9.00-23.1; p0.0001), respectively. CCD had the highest OR, both for internal (23.910.0-56.3; p0.0001) and external controls (24.913.6-45.6; p0.0001). SMAD6tv were also significantly enriched in CHD and PAH/HHT, with more modest OR values (see table). Cosegregation was evaluated in 8 families (a variant confirmed to be "de novo"), identifying 11 additional carriers, of which four (36.4%) had cardiac involvement. Mean age at diagnosis of carries was 38 years, and 62% were male. Sixteen carriers developed CCD and nine required a pacemaker (31%). Regarding CHD, six carriers had a bicuspid aortic valve (BAV). The event rate was low and only two patients suffered sudden cardiac death. Conclusions We demonstrated for the first time a clear association of SMAD6tv with the development of CCD, with a high rate of pacemaker implantation in carriers. The previous association with CHD, especially BAV was also confirmed. SMAD6tv was also enriched in PAH/HHT, suggesting a low penetrance, which should be evaluated in studies with larger cohorts. SMAD6 should be routinely included in genetic panels performed on patients with bradyarrhythmias and congenital heart diseases.