Abstract
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 AscAA 5–8 , 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.
| Original language | English |
|---|---|
| Journal | Nature Genetics |
| Volume | 51 |
| Issue number | 1 |
| Pages (from-to) | 42-50 |
| Number of pages | 9 |
| ISSN | 1061-4036 |
| DOIs | |
| Publication status | Published - 01.01.2019 |
Funding
We gratefully acknowledge support from the Leducq Foundation to A.S.M. and H.C.D., from the National Human Genome Research Institute (NHGRI) (1U54HG006542) to D.V. and J.L., from the National Heart, Lung, and Blood Institute (NHLBI) (HL110328, HL128745) and the NIH (S10OD012287) to J.T.B. We also thank the American Philosophical Society for support of H.A. through the Daland Fellowship. In addition, we thank Johns Hopkins University School of Medicine, McKusick Nathans Institute of Genetic Medicine Center for Functional Investigation in Zebrafish (FINZ) for their technical support and Corinne Boehm for her assistance in depositing variant information to ClinVar. B.L.L. is senior clinical investigator of the Fund for Scientific Research, Flanders, and holds a starting grant from the European Research Council (ERC-StG-2012-30972-BRAVE). A.V. is a postdoctoral researcher supported by the Fund for Scientific Research Flanders. I.L. is supported by a PhD grant from the Agency for Innovation by Science and Technology (IWT). M.E.L. is supported by the Toomey Fund for Aortic Dissection Research and the Fredman Fellowship in Aortic Disease. G.A. is a FQRS Senior Clinical Research Fellow.
