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

Abstract

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 <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.

Genetics of aortic valve disease

“…This association was based on studying two families with autosomal dominant AVD and was supported by the knowledge that Notch signalling is critical for normal heart development in animal models [20,21]. Subsequently, numerous predicted pathogenic NOTCH1 variants have been associated with a spectrum of CHDs including tetralogy of Fallot (TOF), ventricular septal defect (VSD), hypoplastic left heart syndrome (HLHS), coarctation of the aorta (CoA) [22][23][24][25][26][27][28][29][30][31]. Recently, pathogenic variants in the NOTCH regulator MIB1 were found in familial left ventricular noncompaction (LVNC) by exome sequencing.…”

Coarctation of the Aorta: Modern Paradigms Across the Lifespan

“…Mutations in NOTCH1 are associated with left-sided obstructive lesions including CoA. 20 NOTCH1 is important in endothelial cell development and cell-type transition and migration. The initial associations were discovered in families with clustering of CoA and other lesions; these mutations are generally felt to be autosomal dominant.…”

“…The initial associations were discovered in families with clustering of CoA and other lesions; these mutations are generally felt to be autosomal dominant. 7,18,20,21 Turner Syndrome (Monosomy X)…”

Genetics of bicuspid aortic valve: ready for clinical use?

“…In order to delve into the implications of pathogenic NOTCH1 variants in the pathophysiology of BAV, Debiec et al 7 evaluated the incidence of familial and sporadic cases of BAV associated with this gene and their association with congenital cardiac lesions. Also, they reviewed recent publications to provide an overview of the contribution of NOTCH1 in congenital heart diseases.…”