Functional characterisation and pathological significance of variants of MEF2C promoter in tetralogy of Fallot

*MEF2C* promoter variants reducing transcriptional activity and disrupting transcription factor binding

Targeted sequencing of the MEF2C promoter was performed in 305 tetralogy of Fallot patients and 306 controls. Five variants were identified exclusively in patients; four significantly reduced transcriptional activity (from 56.5% to 87.8% of wild-type) in luciferase assays. Bioinformatic analyses and EMSA confirmed that these variants alter transcription factor binding sites (ETS1, GATA3, NFATC2) and disrupt DNA-protein interactions. This study provides the first functional evidence that MEF2C promoter variants are associated with tetralogy of Fallot.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The main interest is drawing attention to noncoding regulatory variants in the MEF2C promoter, usually outside the scope of coding-sequence-centered analyses. The functional demonstration (luciferase + EMSA) is sound, but individual causal effect remains modest for a multifactorial heart defect such as tetralogy of Fallot. A useful reminder that the noncoding regulatory genome deserves interrogation, without immediate diagnostic impact.