Tan et al. (2012) studied 2 patients with aortic valve disease. One was a man who at 30 years of age was undergoing evaluation for hypertension and was found to have a bicuspid aortic valve with mild aortic ... Tan et al. (2012) studied 2 patients with aortic valve disease. One was a man who at 30 years of age was undergoing evaluation for hypertension and was found to have a bicuspid aortic valve with mild aortic stenosis and aortic coarctation. He underwent repair of the coarctation, and subsequently developed significant aortic stenosis and underwent aortic valve replacement and re-repair of the aortic arch. At that time it was noted that the transverse aortic arch, proximal to and distant from the previous conduit, was heavily calcified. There was no evidence of inappropriate calcification in noncardiovascular tissues. The other patient studied by Tan et al. (2012) presented with a heart murmur at 18 months of age and was found to have bicuspid aortic valve with moderate aortic stenosis, without evidence of coarctation.
In a discovery cohort of 90 patients with cardiovascular malformations, Tan et al. (2012) analyzed the candidate genes BMPR2 (600799), BMPR1A (601299), and SMAD6 (602931), and identified a missense mutation in the MH2 domain of the SMAD6 protein ... In a discovery cohort of 90 patients with cardiovascular malformations, Tan et al. (2012) analyzed the candidate genes BMPR2 (600799), BMPR1A (601299), and SMAD6 (602931), and identified a missense mutation in the MH2 domain of the SMAD6 protein (C484F; 602931.0001) in a man with bicuspid aortic valve, aortic valve stenosis, and coarctation and calcification of the aorta. No mutations were identified in BMPR2 or BMPR1A in the cohort. Resequencing of the MH2 domain of SMAD6 in a replication cohort consisting of 346 additional probands with a broad range of cardiovascular malformation phenotypes revealed another missense mutation (P415L; 602931.0002) in an infant with bicuspid aortic valve and moderate aortic stenosis. A third missense mutation, A325T, was identified in a patient with mitral valve prolapse, but in contrast to the other 2 mutated residues, A325 does not have a high degree of evolutionary conservation, and functional analysis showed similar activity to that of wildtype SMAD6. None of the mutations were found in 1,000 Caucasian controls of British ancestry, in 629 individuals in the 1000 Genomes project, or in 200 individuals in the Danish Exome Project.