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

Molecular Genetics & Genomic Medicine

Stephen E. Hamby¹  Sue Coolman¹  Shireen Kharodia¹  Tom R. Webb¹  Aidan Bolger¹  Peter D. Jones¹  Nilesh J. Samani¹  Radoslaw Debiec¹  Manish Asiani¹  Gregory J. Skinner² 

[1] Department of Cardiovascular Sciences University of LeicesterNIHR (National Institute for Health Research) Leicester Biomedical Research CentreGlenfield Hospital Leicester UK;East Midlands Congenital Heart Centre Glenfield Hospital Leicester UK;

关键词: bicuspid aortic valve;    exome sequencing;    NOTCH1;   

DOI  :  10.1002/mgg3.1437

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown