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. 2020 Oct;8(10):e1406.
doi: 10.1002/mgg3.1406. Epub 2020 Aug 3.

Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease

Fadi I Musfee  1 , Dongchuan Guo  2 , Amélie C Pinard  2 , Ellen M Hostetler  2 , Elizabeth E Blue  3 , Deborah A Nickerson  4 ; University of Washington Center for Mendelian Genomics (UW-CMG); Michael J Bamshad  4   5 , Dianna M Milewicz  2 , Siddharth K Prakash  2
Affiliations

Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease

Fadi I Musfee et al. Mol Genet Genomic Med. 2020 Oct.

Abstract

Background: Bicuspid aortic valve (BAV) is the most common cardiovascular malformation in adults, with a prevalence of 0.5%-2%. The prevalence of BAV in cohorts who were ascertained due to thoracic aortic aneurysms or acute aortic dissections (TAD) is as high as 20%. However, the contribution of causal BAV genes to TAD is not known. Therefore, we evaluated rare deleterious variants of GATA4, NOTCH1, SMAD6, or ROBO4 in patients with BAV who presented with TAD.

Methods: Our cohort consisted of 487 probands with Heritable Thoracic Aortic Aneurysms or Dissections (HTAD, 12% BAV, 29% female) and 63 probands with Early onset complications of Bicuspid Aortic Valve disease (EBAV, 63% TAD, 34% female). After whole exome sequencing, we functionally annotated GATA4, NOTCH1, SMAD6, and ROBO4 variants and compared the prevalence of rare variants in these genes to controls without HTAD.

Results: We identified 11 rare deleterious variants of GATA4, SMAD6, or ROBO4 in 12 (18%) EBAV cases. The burden of rare SMAD6 and GATA4 variants was significantly enriched in EBAV but not in HTAD cases, even among HTAD cases with BAV (p < .003).

Conclusion: Rare variants of NOTCH1, ROBO4, SMAD6, or GATA4 do not significantly contribute to BAV in cohorts with HTAD. We conclude that BAV patients who present with HTAD are a genetically distinct subgroup with implications for genetic testing and prognosis.

Keywords: bicuspid aortic valve; thoracic aortic aneurysm; whole exome sequence.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

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