Document Detail


Genotype-phenotype correlation in patients with bicuspid aortic valve and aneurysm.
MedLine Citation:
PMID:  23102684     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Kathleen C Kent; Melissa L Crenshaw; Denise L M Goh; Harry C Dietz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-23
Journal Detail:
Title:  The Journal of thoracic and cardiovascular surgery     Volume:  146     ISSN:  1097-685X     ISO Abbreviation:  J. Thorac. Cardiovasc. Surg.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-17     Completed Date:  2013-08-19     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  0376343     Medline TA:  J Thorac Cardiovasc Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  158-165.e1     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Aortic Aneurysm / complications*,  genetics*
Aortic Valve / abnormalities
Child
Female
Genetic Association Studies*
Heart Valve Diseases
Humans
Male
Mutation*
Pedigree
Receptor, Notch1 / genetics*
Young Adult
Grant Support
ID/Acronym/Agency:
AR41135/AR/NIAMS NIH HHS; AR49698/AR/NIAMS NIH HHS; P01 AR049698/AR/NIAMS NIH HHS; R01 AR041135/AR/NIAMS NIH HHS; //Howard Hughes Medical Institute; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Receptor, Notch1
Comments/Corrections

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