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J Thorac Cardiovasc Surg 2007;134:290-296
© 2007 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms

^a Department of Surgery/Division of Cardiovascular Surgery, Mayo Clinic College of Medicine, Rochester, Minn
^b Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics/Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, Minn.

Received for publication October 24, 2006; revisions received January 22, 2007; accepted for publication February 15, 2007.

^_* Address for reprints: Thoralf M. Sundt III, MD, Division of Cardiovascular Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905. (Email: sundt.thoralf{at}mayo.edu).

Objectives: Bicuspid aortic valve is a common condition and is associated with a significantly increased risk of developing thoracic aortic aneurysms and acute aortic dissection. Patient-specific prediction of the risk of developing thoracic aortic aneurysm, however, is imprecise. We hypothesize that genotypic variations in patients with bicuspid aortic valves contribute to this observed variability in aortic phenotype. We, therefore, investigated the potential relationship between mutations in regions of NOTCH1 recently reported to be associated with bicuspid aortic valve and the phenotype of bicuspid aortic valve and thoracic aortic aneurysms in unrelated patients undergoing surgical repair.

Methods: We performed a targeted mutational analysis of NOTCH1 using genomic DNA from 48 unrelated subjects with concomitant bicuspid aortic valve and thoracic aortic aneurysm using denaturing high-performance liquid chromatography and DNA sequencing. We focused on exons in which mutations associated with bicuspid aortic valve have been reported previously. Results were compared with control subjects with trileaflet aortic valves (n = 94), bicuspid aortic valves, and normal aortas (n = 22) and in subjects with tricuspid aortic valves and thoracic aortic aneurysms (n = 28).

Results: Four unique, nonsynonymous (3 novel) variants were identified in 5 (10.4%) of 48 patients with concomitant bicuspid aortic valves and thoracic aortic aneurysms compared with only 3 (2.1%) of 144 control subjects (P = .02). Of these, 2 novel missense mutations, A1343V and P1390T, were observed only in patients with bicuspid aortic valves and tricuspid aortic aneurysms.

Conclusions: This targeted analysis involving NOTCH1 exons previously implicated in familial and sporadic bicuspid aortic valve demonstrates overrepresentation of NOTCH1 missense variants among patients with bicuspid aortic valves and thoracic aortic aneurysms. Identification of aneurysm-predisposing susceptibility genes may lead to gene-directed surgical therapy of the ascending aorta for patients with bicuspid aortic valves.

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