Rare Genetic Variants in Gata Transcription Factors in Patients with Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a very heterogeneous disease. Although primarily caused by mutations in genes encoding sarcomeric proteins, other genes might explain that heterogeneity. Potential candidate genes are GATA transcription factors that regulate the expression of proteins associated with HCM. Exons of ,, and genes were sequenced in 212 patients with unrelated HCM previously analyzed for genes encoding the most frequently mutated sarcomeric proteins. Functional effects of variants were predicted by in silico analyses. 3 potentially pathogenic variants were identified: c.-77G>A in , p.Ala343Thr (rs370588269) in, and p.Pro555Ala (rs146243018) in Multivariate analyses showed that angina was more frequent in patients carrying sarcomeric and GATA rare variants (55% vs 23.2% in non-carriers of GATA rare variants, OR (95% CI) 7.12 (1.23 to 41.27), p=0.029). Among patients without a known causal mutation, GATA rare variants were associated with a greater maximum posterior wall thickness (16.4±4.4 vs 14.0±3.1 mm in non-carriers, p=0.021). Thus, variants having a putative effect on GATA genes would alter the expression of their target genes and could modify the hypertrophic response. Therefore, although relatively infrequent in patients with HCM, they may represent a novel insight into the molecular mechanisms related to the pathogenesis of HCM.

Unusual Cause of Bidirectional Ventricular Rhythm

“…In the present study, both the child and his father harbored the same variation in TTN and KCNH2 gene, but the father lacked the variation in the GATA4 gene, which could have influenced the selective expression of disease phenotype in the proband. Thus, the GATA4 variation could be acting as a genetic modifier in the patient, as previously reported for patients with HCM (18) .…”

Systemic Bioinformatic Analyses of Nuclear-Encoded Mitochondrial Genes in Hypertrophic Cardiomyopathy

“…Previous studies have underscored the pivotal roles of the GATA family in cardiac hypertrophy ( Pikkarainen et al, 2004 ). Mutations in GATA2 , GATA4 , and GATA6 were identified in patients with HCM ( Alonso-Montes et al, 2017 ). Overexpression of either GATA4 or GATA6 could induce cardiac hypertrophy both in vitro and in vivo ( Liang et al, 2001 ).…”

Variants in cardiac GATA genes associated with bicuspid aortic valve

“…Identified variants were classified as rare and potentially BAV‐related accordingly to previous criteria . In these variants, the potential pathogenic effect was studied.…”