ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%)1-3 that frequently presents with ascending aortic aneurysm (AscAA)4. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA5-8, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

Intima-media thickness of the descending aorta in patients with bicuspid aortic valve.

OBJECTIVE: A bicuspid aortic valve (BAV) is associated with accelerated aortic valve disease (AVD) and abnormalities in aortic elasticity. We investigated the intima-media thickness of the descending aorta (AoIMT) in patients with AVD with or without an ascending aortic aneurysm (AscAA), in relation to BAV versus tricuspid aortic valve (TAV) phenotype, type of valve disease, cardiovascular risk factors, and single-nucleotide polymorphisms (SNPs) with a known association with carotid IMT. METHODS AND RESULTS: 368 patients (210 with BAV, 158 with TAV,); mean age 64 ± 13 years) were examined using transesophageal echocardiography (TEE) before valvular and/or aortic surgery. No patient had a coronary disease (CAD). The AoIMT was measured on short-axis TEE images of the descending aorta using a semi-automated edge-detection technique. AoIMT was univariately (P < 0.05) related to age, blood pressure, smoking, creatinine, highly sensitive C-reactive protein, HDL, valve hemodynamics and BAV. In the TAV subgroup it was also associated with the rs200991 SNP. Using multivariate regression analysis, age was the main determinant for AoIMT (P < 0.001), followed by male gender (P = 0.02), BAV was no longer a significant predictor of AoIMT. AoIMT was still related to the rs200991 SNP in TAV (P = 0.034), and to creatinine in BAV (P = 0.019), when other variables were accounted for. CONCLUSIONS: Intima-media thickness of the descending aorta is not affected by aortic valve morphology (BAV/TAV); age is the main determinant of AoIMT. Genetic markers (SNPs) known to influence IMT in the carotid artery seem to correlate to IMT in the descending aorta only in patients with TAV.