GATA6 – Conotruncal Heart Malformations

Multiple lines of evidence support a significant association between heterozygous GATA6 variants and conotruncal heart malformations. In an exome cohort of 245 nonsyndromic conotruncal cardiac defect patients, rare and ultrarare protein-altering GATA6 variants were enriched compared with ethnicity-matched controls, implicating GATA6 among four candidate genes for clinical testing (PMID:36789878).

Targeted sequencing of 542 conotruncal defect probands identified GATA6 variants in 11 individuals (2.0% frequency), including a novel frameshift c.1254del (p.Ser418ArgfsTer3), absent in 400 controls. Functional assays demonstrated that the p.Ser418ArgfsTer3 mutant fails to transactivate cardiac promoters and mislocalizes within the cell, consistent with loss of function (PMID:29101065).

Early studies in persistent truncus arteriosus patients identified two distinct GATA6 missense and frameshift mutations that abrogate semaphorin-plexin signaling, key to outflow tract development. Both mutant proteins failed to activate SEMA3C and PLXNA2 promoters, linking GATA6 loss to conotruncal phenotypes (PMID:19666519).

Inheritance is autosomal dominant with reduced penetrance; no large multi-generation pedigrees have shown extensive segregation of GATA6 variants in conotruncal malformations (affected relatives = 0). To date, at least 16 unrelated probands carry likely pathogenic GATA6 variants across three cohorts, comprising frameshift and missense changes in the zinc-finger domains.

Functional characterization in human iPSC-derived cardiomyocytes and mouse models demonstrates that GATA6 acts as a pioneer transcription factor in outflow tract morphogenesis. GATA6 binds a cis-regulatory element in TBX1 intron 1 to drive TBX1 expression, coupling Notch and RA signaling pathways. Loss-of-function variants impair enhancer occupancy and reduce TBX1 transcription, recapitulating conotruncal defects in vivo (PMID:34332615).

Taken together, genetic burden analyses, case series, and concordant functional assays establish a Strong gene–disease association. Mechanistically, GATA6 haploinsufficiency disrupts transcriptional networks essential for outflow tract septation and alignment. GATA6 screening is recommended for diagnostic panels in conotruncal malformations.

References

• Journal of the American Heart Association • 2023 • Evaluating High-Confidence Genes in Conotruncal Cardiac Defects by Gene Burden Analyses PMID:36789878
• Proceedings of the National Academy of Sciences of the United States of America • 2009 • GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling PMID:19666519
• Gene • 2018 • Targeted sequencing identifies novel GATA6 variants in a large cohort of patients with conotruncal heart defects PMID:29101065
• Orphanet Journal of Rare Diseases • 2021 • Variants in a cis-regulatory element of TBX1 in conotruncal heart defect patients impair GATA6-mediated transactivation PMID:34332615

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