BVES – Tetralogy of Fallot

Emerging evidence implicates BVES in non-syndromic tetralogy of Fallot (Tetralogy of Fallot). In a Chinese cohort of 114 unrelated TOF probands, four novel BVES variants (c.166T>C (p.Leu56=), c.909C>T (p.Asp303=), c.540-80C>T and c.958+30A>G) were identified exclusively in cases and absent in 400 healthy controls (PMID:23403794). A subsequent case–control study of 146 TOF patients versus 100 controls detected the missense SNP c.385C>T (p.Arg129Trp) at a higher frequency in cases (0.035% vs 0.025%) and predicted deleterious by PolyPhen2 and SIFT (PMID:31386585). No familial segregation data are available. Based on rarity in controls and lack of segregation, the overall gene–disease association is classified as Limited.

Functional characterization using luciferase reporter assays demonstrated that c.166T>C enhances BVES promoter activity while c.385C>T reduces BVES expression and downstream GATA4/NKX2.5 promoter activity, consistent with a role in cardiomyocyte differentiation and outflow tract development (PMID:23403794; PMID:31386585). These in vitro data support a regulatory mechanism of pathogenicity but lack in vivo or segregation validation.

Key take-home: BVES exhibits limited clinical validity for TOF via regulatory variants affecting transcription, meriting further genetic and mechanistic studies to clarify its diagnostic utility.

References

• International journal of molecular medicine • 2013 • Mutational and functional analysis of the BVES gene coding region in Chinese patients with non-syndromic tetralogy of Fallot. PMID:23403794
• Genetic testing and molecular biomarkers • 2019 • The Functional Polymorphism R129W in the BVES Gene Is Associated with Sporadic Tetralogy of Fallot in the Han Chinese Population. PMID:31386585

Evidence Based Scoring (AI generated)