Aortic Valve Disease 2

A number sign (#) is used with this entry because of evidence that aortic valve disease-2 (AOVD2) is caused by heterozygous mutation in the SMAD6 gene (602931) on chromosome 15q22.

Aortic valve disease-2 (AOVD2) is characterized by bicuspid aortic valve (BAV) and dilation of the ascending aorta. Calcification of the valve and the aorta has been observed, and some patients exhibit coarctation of the aorta (Tan et al., 2012; Luyckx et al., 2019; Park et al., 2019).

For a general phenotypic description and a discussion of genetic heterogeneity of aortic valve disease, see AOVD1 (109730).

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.

Park et al. (2019) reported a 42-year-old Korean man with ascending aorta dilation in whom echocardiography revealed a severely calcified bicuspid aortic valve. CT angiography showed significant dilation of the ascending aorta, with a diameter of 5.5 cm, and confirmed dense calcification in the aortic valve. By echocardiography of the aortic root, the aortic valve annulus was measured at 2.5 cm, the sinus of Valsalva at 3.1 cm, and the sinotubular junction at 3.3 cm. The BAV was of the lateral subtype. There was no family history of cardiovascular disease.

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.

Luyckx et al. (2019) studied 473 unrelated patients with nonsyndromic thoracic aortic aneurysm (AAT), who were all negative for mutation in known AAT genes, and 65 of whom also had bicuspid aortic valve. SMAD6-targeted resequencing identified 6 probands with likely pathogenic variants (see, e.g., 602931.0006 and 602931.0007), all of whom were individuals with BAV/AAT. Familial segregation studies demonstrated reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity.

In a 42-year-old Korean man with a severely calcified BAV and aneurysm of the ascending aorta, Park et al. (2019) screened 20 BAV-associated genes and identified heterozygosity for a 6-bp in-frame duplication in the SMAD6 gene (602931.0008). The mutation was not found in his unaffected mother or brother, or in public variant databases; no DNA was available from his father, who died of bladder cancer at age 69 years and had no history of cardiovascular disease.