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

First Author	Gould RA	Year	2019
Journal	Nat Genet	Volume	51
Issue	1	Pages	42-50
PubMed ID	30455415	Mgi Jnum	J:292067
Mgi Id	MGI:6447627	Doi	10.1038/s41588-018-0265-y
Citation	Gould RA, et al. (2019) ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nat Genet 51(1):42-50

abstractText

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.

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

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