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

Stephen H. McKellar, David J. Tester, Marineh Yagubyan, Ramanath Majumdar, Michael John Ackerman, Thoralf M. Sundt

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)290-296
Number of pages7
JournalJournal of Thoracic and Cardiovascular Surgery
Volume134
Issue number2
DOIs
StatePublished - Aug 2007

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Thoracic Aortic Aneurysm
Aortic Diseases
Mutation
Aortic Valve
Aorta
Bicuspid Aortic Valve
Exons
Phenotype
Tricuspid Valve
Aortic Aneurysm
Missense Mutation
DNA Sequence Analysis
Genes
Aneurysm
Dissection

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. / McKellar, Stephen H.; Tester, David J.; Yagubyan, Marineh; Majumdar, Ramanath; Ackerman, Michael John; Sundt, Thoralf M.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 134, No. 2, 08.2007, p. 290-296.

Research output: Contribution to journalArticle

McKellar, Stephen H. ; Tester, David J. ; Yagubyan, Marineh ; Majumdar, Ramanath ; Ackerman, Michael John ; Sundt, Thoralf M. / Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. In: Journal of Thoracic and Cardiovascular Surgery. 2007 ; Vol. 134, No. 2. pp. 290-296.
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AU - Ackerman, Michael John

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AB - 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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