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

7 Citations (Scopus)

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 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.

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

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Thoracic Aortic Aneurysm
Aortic Aneurysm
Congenital Heart Defects
Penetrance
Endothelial Cells
Animal Models
Bicuspid Aortic Valve
Phenotype
Cell Line
Mutation
Incidence
Population
Genes

ASJC Scopus subject areas

  • Genetics

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

ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. / Baylor-Hopkins Center for Mendelian Genomics; MIBAVA Leducq Consortium.

In: Nature genetics, Vol. 51, No. 1, 01.01.2019, p. 42-50.

Research output: Contribution to journalLetter

Baylor-Hopkins Center for Mendelian Genomics & MIBAVA Leducq Consortium 2019, 'ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm', Nature genetics, vol. 51, no. 1, pp. 42-50. https://doi.org/10.1038/s41588-018-0265-y
Baylor-Hopkins Center for Mendelian Genomics, MIBAVA Leducq Consortium. ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nature genetics. 2019 Jan 1;51(1):42-50. https://doi.org/10.1038/s41588-018-0265-y
Baylor-Hopkins Center for Mendelian Genomics ; MIBAVA Leducq Consortium. / ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. In: Nature genetics. 2019 ; Vol. 51, No. 1. pp. 42-50.
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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 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.",
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AU - Lino Cardenas, Christian Lacks

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N2 - 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.

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