Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions

Autor: Radoslaw Marek Debiec, Stephen E Hamby, Peter D Jones, Kassem Safwan, Michael Sosin, Simon Lee Hetherington, David Sprigings, David Sharman, Kelvin Lee, Pegah Salahshouri, Nigel Wheeldon, Andrew Chukwuemeka, Vasiliki Boutziouka, Mohamed Elamin, Sue Coolman, Manish Asiani, Shireen Kharodia, Gregory J Skinner, Nilesh J Samani, Tom R Webb, Aidan P Bolger
Rok vydání: 2022
Předmět:
Zdroj: Heart. 108:1114-1120
ISSN: 1468-201X
1355-6037
DOI: 10.1136/heartjnl-2021-320428
Popis: IntroductionBicuspid aortic valve (BAV) affects 1% of the general population. NOTCH1 was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to NOTCH1 mutations has not been estimated.AimThe aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to NOTCH1 mutations.MethodsThe population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research—8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent NOTCH1 sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting NOTCH1 sequencing in context of congenital heart disease.ResultsNOTCH1 sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic NOTCH1 variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting NOTCH1 sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic NOTCH1 variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic NOTCH1 mutations was observed in almost half of reported pedigrees.ConclusionsPathogenic and likely pathogenic NOTCH1 genetic variants explain 2% of familial and
Databáze: OpenAIRE
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