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Novel loss of function mutation in NOTCH1 in a family with bicuspid aortic valve, ventricular septal defect, thoracic aortic aneurysm, and aortic valve stenosis

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posted on 10.05.2021, 09:42 by Radoslaw Debiec, Stephen E Hamby, Peter D Jones, Sue Coolman, Manish Asiani, Shireen Kharodia, Gregory J Skinner, Nilesh J Samani, Tom R Webb, Aidan Bolger
Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC Background: Bicuspid aortic valve is the most common congenital valvular heart defect in the general population. BAV is associated with significant morbidity due to valve failure, formation of thoracic aortic aneurysm, and increased risk of infective endocarditis and aortic dissection. Loss of function mutations in NOTCH1 (OMIM 190198) has previously been associated with congenital heart disease involving the aortic valve, left ventricle outflow tract, and mitral valve that segregates in affected pedigrees as an autosomal dominant trait with variable expressivity. Methods: We performed whole-exome sequencing in four members of a three-generational family (three affected and one unaffected subject) with clinical phenotypes including aortic valve stenosis, thoracic aortic aneurysm, and ventricular septal defect. Results: We identified 16 potentially damaging genetic variants (one stop variant, one splice variant, and 14 missense variants) cosegregating with the phenotype. Of these variants, the nonsense mutation (p.Tyr291*) in NOTCH1 was the most deleterious variant identified and the most likely variant causing the disease. Conclusion: Inactivating NOTCH1 mutations are a rare cause of familial heart disease involving predominantly left ventricular outflow tract lesions and characterized by the heterogeneity of clinical phenotype.

Funding

The study was supported by the NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. RD is funded by the NIHR. NJS and TRW are supported by the British Heart Foundation. British Heart Foundation. Grant Number: SP/16/4/32697

History

Citation

Debiec, R, Hamby, SE, Jones, PD, et al. Novel loss of function mutation in NOTCH1 in a family with bicuspid aortic valve, ventricular septal defect, thoracic aortic aneurysm, and aortic valve stenosis. Mol Genet Genomic Med. 2020; 8:e1437. https://doi.org/10.1002/mgg3.1437

Version

VoR (Version of Record)

Published in

Molecular Genetics and Genomic Medicine

Volume

8

Pagination

e1437

Publisher

Wiley Open Access

issn

2324-9269

eissn

2324-9269

Acceptance date

09/07/2020

Copyright date

2020

Available date

10/05/2021

Spatial coverage

United States

Language

English