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.

Additional Metadata
Persistent URL,
Journal Nature Genetics
Gould, R.A. (Russell A.), Aziz, H. (Hamza), Woods, C.E. (Courtney E.), Seman-Senderos, M.A. (Manuel Alejandro), Sparks, E. (Elizabeth), Preuss, C. (Christoph), … Dietz, H.C. (Harry C.). (2018). ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nature Genetics. doi:10.1038/s41588-018-0265-y