Functional noncoding variants within the TBX1 enhancer contribute to tetralogy of Fallot.

Functional noncoding variants in the TBX1 enhancer (EnhTBX1) reducing TBX1 expression; impaired angiogenesis and outflow-tract formation via DLL4 and TGFBR2.

Whole-genome sequencing (WGS) of 428 patients with tetralogy of Fallot (TOF) identified a 22q11.2 deletion in 31 cases and seven functional noncoding variants in the TBX1 enhancer (EnhTBX1), together accounting for 9.81 % of cases. Deleting EnhTBX1 in ES cells, modelled in blood-vessel organoids, markedly reduced TBX1 expression, impairing angiogenesis and pericyte coverage. Mechanistically, TBX1 acts as a transcription factor for endothelial progenitors, targeting angiogenesis genes such as DLL4 and TGFBR2. Overexpressing TBX1 rescued these phenotypes.

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

A study that perfectly illustrates why WGS and regulatory-region interpretation matter: noncoding enhancer variants, invisible to a coding panel, explain nearly 10 % of a major heart defect, with a convincing organoid functional demonstration. It is a strong argument for systematically annotating known enhancers in diagnostics. Routine translation will depend on the robustness of interpreting these regulatory variants.

Analysis by Dr Thibaut Benquey