GATA5 – Familial Atrial Fibrillation

Familial atrial fibrillation (AF) is an inheritable cardiac arrhythmia characterized by disorganized atrial electrical activity. GATA5 (HGNC:15802) encodes a zinc-finger transcription factor involved in cardiac development and homeostasis. A sequencing study of 110 unrelated familial AF probands and 200 healthy controls identified two novel heterozygous GATA5 missense variants underlying disease susceptibility.

Genetic analysis revealed two missense mutations—c.628T>G (p.Cys210Gly) and c.413A>T (p.Tyr138Phe)—in two of the 110 pedigrees; both variants were absent in 400 control alleles and affected completely conserved residues (PMID:23295592). These variants co-segregated with AF in each family, consistent with autosomal dominant inheritance.

Segregation data include at least two affected relatives per family (total 4 individuals) carrying the mutant alleles, confirming familial clustering. No truncating, splice or structural variants were reported, and no founder or recurrent alleles have been described to date.

Functional assays using a luciferase reporter system demonstrated that both p.Cys210Gly and p.Tyr138Phe mutants significantly reduce transcriptional activation compared with wild-type GATA5, supporting a loss-of-function mechanism (PMID:23295592).

No conflicting studies have been reported for GATA5 monogenic causality in familial AF. However, complex inheritance involving additional loci may modulate penetrance.

Integration of genetic and functional data yields a limited but credible association between GATA5 variants and familial AF. Targeted GATA5 sequencing can aid risk assessment and early prophylaxis in affected families.

References

• Clinics (Sao Paulo, Brazil) • 2012 • Novel GATA5 loss-of-function mutations underlie familial atrial fibrillation. PMID:23295592

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