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GATA5 encodes a zinc-finger transcription factor essential for cardiogenesis. An initial study screened NOTCH1, GATA5, TGFBR1 and TGFBR2 in 11 Italian families with autosomal dominant familial bicuspid aortic valve (BAV) but found no pathogenic GATA5 variants in coding or regulatory regions, despite segregation analysis and control screening (PMID:23578328). In contrast, a subsequent study sequenced GATA5 in 110 unrelated BAV patients and identified two novel heterozygous loss-of-function mutations, c.46T>G (p.Tyr16Asp) and c.754A>C (p.Thr252Pro), each segregating with autosomal dominant BAV in two families, absent in 400 control chromosomes, and demonstrating significantly reduced transcriptional activity in luciferase assays (PMID:24638895).
These conflicting findings between a negative screening in multiple families and positive segregation with functional impact yield a disputed association of GATA5 with familial BAV. Further large-scale sequencing and functional studies are required to clarify GATA5’s role in BAV pathogenesis. Key Take-home: current evidence is insufficient to support routine GATA5 testing for familial BAV in clinical diagnostics.
Gene–Disease AssociationDisputedOne study screened 11 familial BAV cases without finding pathogenic GATA5 variants (PMID:23578328); another identified two LoF mutations segregating in two families with functional impairment (PMID:24638895), yielding conflicting evidence. Genetic EvidenceLimitedTwo heterozygous loss-of-function variants co-segregating in two families with autosomal dominant BAV, absent from controls, but lack of replication in additional familial cohorts. Functional EvidenceLimitedIn vitro luciferase assays demonstrated significantly reduced transcriptional activity of GATA5 mutants associated with BAV. |