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

Abstract

Bicuspid aortic valve (BAV) affects 1% of the general population. <i>NOTCH1</i> was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to <i>NOTCH1</i> mutations has not been estimated. The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to <i>NOTCH1</i> mutations. The 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 <i>NOTCH1</i> sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting <i>NOTCH1</i> sequencing in context of congenital heart disease. <i>NOTCH1</i> 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 <i>NOTCH1</i> variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting <i>NOTCH1</i> sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic <i>NOTCH1</i> 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 <i>NOTCH1</i> mutations was observed in almost half of reported pedigrees. Pathogenic and likely pathogenic <i>NOTCH1</i> genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.