Genetic analysis of the Irx4 gene in hypertrophic cardiomyopathy

The Irx4 gene is predominantly expressed in cardiac ventricles. It has been demonstrated in animal studies that disruption of the Irx4 gene causes inhibition of chamber-specific expression of myosin heavy chain genes, resulting in abnormal ventricular gene expression and cardiac hypertrophy. In this study, we aimed to investigate a possible association between mutations in the Irx4 gene and hypertrophic cardiomyopathy (HC).

The study included 68 patients (32 females, 36 males; mean age 49 years; range 17 to 74 years) with HC and 67 healthy controls (33 females, 34 males; mean age 45 years; range 20 to 88 years). All the patients were evaluated with a detailed history, physical examination, 12-lead electrocardiography, and transthoracic echocardiography. DNA samples of all the subjects were extracted. Genomic DNA fragments were amplified by polymerase chain reaction and screened by single-strand conformation polymorphism analysis. DNA sequences were determined through an automated sequencing system.

All exons in the Irx4 gene were examined. No mutations were detected associated with HC. Four polymorphisms were identified including G355>A, A381>G, G1203>A, and C1431>T. Compared with patients having the GA and GG genotyes, patients with the AA genotype of A381>G polymorphism were found to have a higher maximal left ventricle outflow tract gradient (p=0.03), prolonged corrected QT dispersion (p=0.05), and albeit not statistically significant, increased septal thickness (p=0.07).

This is the first human study investigating the association between the Irx4 gene and HC. Polymorphism A381>G of the Irx4 gene may have a modifier effect on septal thickness, resulting in increased corrected QT dispersion and higher outflow gradients.