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

Authors: Russell A. Gould, Hamza Aziz, Courtney E. Woods, Manuel Alejandro Seman-Senderos, Elizabeth Sparks, Christoph Preuß, Florian Wünnemann, Djahida Bedja, Cassandra Rae Moats, Sarah A. McClymont, Rebecca Rose, Nara Sobreira, Hua Ling, Gretchen MacCarrick, Ajay Kumar, Ilse Luyckx, Elyssa Cannaerts, Aline Verstraeten, Hanna Björk, Ann-Cathrin Lehsau, Vinod Jaskula-Ranga, Henrik Lauridsen, Asad A. Shah, Christopher Bennett, Patrick T. Ellinor, Honghuang Lin, Eric M. Isselbacher, Christian L. Lino Cardenas, Jonathan T. Butcher, G. Chad Hughes, Mark E. Lindsay, Luc Mertens, Anders Franco‐Cereceda, Judith M.A. Verhagen, Marja W. Wessels, Salah A. Mohamed, Per Eriksson, Seema Mital, Lut Van Laer, Bart Loeys, Grégor Andelfinger, Andrew S. McCallion, Harry C. Dietz - Nature Genetics 2018 cited by 153

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. Individuals with biscuspid aortic valve and ascending aortic aneurysm show enrichment of rare variants in ROBO4. Functional studies suggest that ROBO4 mutations disrupt endothelial cell performance and contribute to pathological remodeling of aortic tissues.