A novel NOTCH1 nonsense variant in a bicuspid aortic valve family with intrafamilial clinical heterogeneity.

backgroundBicuspid aortic valve (BAV) represents a prevalent form of congenital heart disease. The NOTCH1 gene is implicated in the pathogenesis of BAV, and congenital valve anomalies caused by variants in this gene are classified as Aortic Valve Disease 1 (AOVD1), which is inherited in an autosomal dominant pattern.

methodsEchocardiographic data and peripheral blood samples were collected from a Chinese family manifesting a clinical phenotype characterized by various cardiovascular abnormalities, including BAV. Exome sequencing target enrichment technology was performed to identify candidate genes and variants. This was followed by family segregation analysis using Sanger sequencing.

resultsA novel nonsense variant, c.2266G > T (p.Glu756Ter), was identified in the NOTCH1 gene (NM_017617.5) within this family. Individuals harboring the p.Glu756Ter pathogenic variant (III4, II7, II9, and I2) exhibited BAV - associated phenotypes. Conversely, the proband carrying p.Glu756Ter pathogenic variant (IV1) presented with distinct clinical phenotypes, including a persistent left superior vena cava (PLSVC) and a widened coronary sinus. Family members without the p.Glu756Ter pathogenic variant showed no cardiovascular abnormalities. This variant is located in exon 14 of the NOTCH1 gene, resulting in a premature stop codon. Bioinformatics analysis predicted that p.Glu756Ter induces nonsense-mediated mRNA decay or produces a truncated protein, impairing NOTCH1 receptor function.

conclusionsThe NOTCH1 variant is a prevalent genetic factor in BAV etiology, exhibiting both interfamilial and intrafamilial phenotypic variability with incomplete penetrance. PLSVC and a widened coronary sinus represent common anatomical variations within the general population. Nevertheless, the potential role of NOTCH1 variants in the development of these vascular anomalies should be considered.