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

作者：Qian Chen, Ziyan Xu, Wu Chi, Xiang Chen, Jing Zou, Ting Chen, Mei X. Wu, Dan‐dan Ruan, Hongping Yu, Jianhui Zhang, Mei-zhu Gao, Li Zhang, Lisheng Liao, Zhu-Ting Fang, Fan Lin, Jie-wei Luo, Li Chen · 发表于：BMC Cardiovascular Disorders · 年份：2025 · DOI：10.1186/s12872-025-05100-0 · 研究领域：Congenital heart defects research、Congenital Heart Disease Studies、Tracheal and airway disorders

BACKGROUND: Bicuspid 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. METHODS: Echocardiographic 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. RESULTS: A 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. CONC...