GATA4 – Tetralogy of Fallot

Evidence for involvement of GATA4 in Tetralogy of Fallot arises from the identification of rare germline and somatic variants in affected individuals. A heterozygous GATA4 mutation was detected in 2 of 26 sporadic ToF patients (PMID:16470721), and a novel somatic stop-gain variant c.708T>G (p.Tyr236Ter) was found in myocardial tissue of one non-familial ToF case (PMID:38274337). No additional affected relatives segregating these variants have been reported.

Functional assays demonstrate that the c.708T>G (p.Tyr236Ter) variant abolishes transactivation of the myosin heavy chain 6 promoter and disrupts synergistic interactions with NKX2-5 and TBX5 in dual-luciferase studies (PMID:38274337). Earlier work showed that GATA4 missense mutations impair DNA binding, reduce transcriptional activity, and weaken interaction with SMAD4 and TBX5 (PMID:12845333). These data are consistent with haploinsufficiency as the pathogenic mechanism but are based on a small number of cases without robust familial segregation.

Key Take-home: Current data support a limited association of GATA4 haploinsufficiency with Tetralogy of Fallot; further studies are needed for diagnostic and clinical utility.

References

• Human mutation | 2006 | A novel mutation in the GATA4 gene in patients with Tetralogy of Fallot PMID:16470721
• Nature | 2003 | GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 PMID:12845333
• Experimental and therapeutic medicine | 2024 | Somatic GATA4 mutation contributes to tetralogy of Fallot PMID:38274337

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