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

Autor: Gregory J Skinner, Shireen Kharodia, Nilesh J. Samani, Sue Coolman, Peter Jones, Manish Asiani, Tom R. Webb, Aidan Bolger, Stephen E Hamby, Radoslaw Debiec
Rok vydání: 2020
Předmět:
Adult
Heart Septal Defects
Ventricular
Male
0301 basic medicine
Aortic valve
medicine.medical_specialty
bicuspid aortic valve
lcsh:QH426-470
030105 genetics & heredity
Thoracic aortic aneurysm
Clinical Reports
03 medical and health sciences
Bicuspid aortic valve
NOTCH1
Bicuspid Aortic Valve Disease
Loss of Function Mutation
Internal medicine
Mitral valve
Genetics
Humans
Medicine
Ventricular outflow tract
Receptor
Notch1
Molecular Biology
Genetics (clinical)
Aged
Aortic dissection
Clinical Report
Aortic Aneurysm
Thoracic
business.industry
Autosomal dominant trait
Aortic Valve Stenosis
Middle Aged
medicine.disease
Pedigree
lcsh:Genetics
Phenotype
030104 developmental biology
medicine.anatomical_structure
Codon
Nonsense
Aortic valve stenosis
cardiovascular system
Cardiology
Female
business
exome sequencing
Zdroj: Molecular Genetics & Genomic Medicine
Molecular Genetics & Genomic Medicine, Vol 8, Iss 10, Pp n/a-n/a (2020)
ISSN: 2324-9269
Popis: 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.
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 revealed nonsense mutation (p.Tyr291*) in NOTCH1. Inactivating NOTCH1 mutations are a rare cause of familial heart disease involving predominantly left ventricular outflow tract lesions and characterized by heterogeneity of clinical phenotype.
Databáze: OpenAIRE
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