GATA5 – Tetralogy of Fallot

GATA5 is a zinc-finger transcription factor critical for cardiac development, regulating endocardial cushion formation and outflow tract morphogenesis. Tetralogy of Fallot (TOF) is a cyanotic congenital heart defect characterized by ventricular septal defect, overriding aorta, pulmonary stenosis and right ventricular hypertrophy. Genetic studies have implicated GATA5 variants as contributors to TOF pathogenesis in both familial and sporadic cases.

Autosomal dominant germline GATA5 loss-of-function mutations, p.Arg187Gly and p.His207Arg, were identified in 2 unrelated TOF families and co-segregated with disease in each pedigree ([PMID:23289003]). No these variants were observed in 400 control chromosomes. In addition, somatic heterozygous GATA5 variants, c.609C>G (p.Asp203Glu) and p.Tyr208Ter, were discovered in cardiac tissue of 2 sporadic TOF patients and absent in blood and in 263 non-TOF controls ([PMID:24573614]).

Segregation analysis demonstrated co-segregation of germline variants with affected relatives in 2 families, confirming autosomal dominant transmission and supporting familial recurrence of TOF. No evidence of these alleles was found in unaffected family members or healthy controls.

Functional assessment using luciferase reporter assays revealed that germline p.Arg187Gly and p.His207Arg mutants exhibited markedly reduced transcriptional activation compared with wild-type GATA5 ([PMID:23289003]). Similarly, p.Asp203Glu and p.Tyr208Ter mutants showed significantly decreased promoter activity in vitro, consistent with a loss-of-function mechanism ([PMID:24573614]).

Mechanistically, GATA5 haploinsufficiency likely disrupts transcriptional networks governing endocardial cushion differentiation and outflow tract alignment, aligning with the phenotypic features of TOF. Experimental data from both germline and somatic variants concordantly demonstrate impaired GATA5 function.

Taken together, moderate clinical validity is supported by 4 unrelated probands (2 germline; 2 somatic), segregation in 2 families, and concordant functional data. GATA5 loss-of-function variants confer autosomal dominant risk for TOF, warranting inclusion in diagnostic gene panels and guiding genetic counselling.

Key Take-home: GATA5 loss-of-function variants moderately support autosomal dominant predisposition to tetralogy of Fallot with robust functional validation.

References

• International journal of medical sciences • 2013 • GATA5 loss-of-function mutations underlie tetralogy of fallot. PMID:23289003
• International journal of molecular medicine • 2014 • Somatic GATA5 mutations in sporadic tetralogy of Fallot. PMID:24573614

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