| Genotype-phenotype correlation in patients with bicuspid aortic valve and aneurysm. | |
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MedLine Citation:
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PMID: 23102684 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVES: Bicuspid aortic valve is the most common congenital cardiac abnormality, occurring in 1% to 2% of the population, and often associates with ascending aortic aneurysm. Based on familial studies, bicuspid aortic valve with aneurysm segregates in an autosomal dominant manner with incomplete penetrance. NOTCH1 mutations have been reported in 6 families with prominent valve calcification and dysfunction and low penetrance of aneurysm. We sought to determine the contribution of NOTCH1 mutations to the more common phenotype of highly penetrant aneurysms with low penetrance of bicuspid aortic valve and with rare valve calcification or dysfunction. METHODS: All exons and splice junctions of NOTCH1 were sequenced in probands from 13 affected families presenting with bicuspid aortic valve with ascending aortic aneurysm in the absence of valve calcification. In addition, mutation analysis was performed on a single individual with aneurysm and calcified tricuspid aortic valve. Sequences were aligned and compared with the reference genomic sequence. RESULTS: Corroborating previous studies, analysis of the single sporadic patient with calcified aortic valve in the presence of ascending aortic aneurysm revealed a novel heterozygous missense mutation in NOTCH1 resulting in a nonsynonymous amino acid substitution (p.T1090S, c.C3269G) of an evolutionarily conserved residue. This change was not observed in controls. In contrast, we did not identify any pathologic NOTCH1 mutations in the 13 families segregating noncalcified bicuspid aortic valve with highly penetrant aortic aneurysm. CONCLUSIONS: These data suggest that there are phenotypic differences that distinguish families with and without NOTCH1 mutations, indicating a genotype-phenotype correlation with potential implications for patient diagnosis, counseling, and management. |
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Authors:
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Kathleen C Kent; Melissa L Crenshaw; Denise L M Goh; Harry C Dietz |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-23 |
Journal Detail:
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Title: The Journal of thoracic and cardiovascular surgery Volume: - ISSN: 1097-685X ISO Abbreviation: J. Thorac. Cardiovasc. Surg. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376343 Medline TA: J Thorac Cardiovasc Surg Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved. |
Affiliation:
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McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Md. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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