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

Baylor-Hopkins Center for Mendelian Genomics, MIBAVA Leducq Consortium

Research output: Contribution to journalLetter

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 languageEnglish (US)
Pages (from-to)42-50
Number of pages9
JournalNature genetics
Volume51
Issue number1
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm'. Together they form a unique fingerprint.

  • Cite this

    Baylor-Hopkins Center for Mendelian Genomics, & MIBAVA Leducq Consortium (2019). ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nature genetics, 51(1), 42-50. https://doi.org/10.1038/s41588-018-0265-y