Objectives: Ventricular septal defect (VSD) is the most common congenital heart disease (CHD). Genome-wide linkage analysis revealed a potential CHD susceptibility locus in the homeodomain leucine zipper-encoding (HOMEZ) gene in a South Indian population. The present study aimed to identify potential pathogenic mutations for HOMEZ and to provide insights into the etiology of isolated VSD in the Chinese population.
Methods: Case-control mutational analysis was performed in 400 patients with isolated VSD and 400 healthy controls. Protein-coding exton of HOMEZ and their flanking sequences were amplified by polymerase chain reaction and sequenced on an ABI3730 Automated Sequencer. CLC workbench software was used to compare the conservatism of the HOMEZ protein with other multiple species. The ExPASy-ProtScale online tool was used to predicate the alignment of the hydrophobic features.
Results: Two novel heterozygous missense mutations (c.116 C>T; c. 630T>A) were identified in HOMEZ gene exon-2. The two mutations lead to alanine to valine substitution at position 39 and serine to arginine at position 210, which are highly conserved among many species. The hydropathicity of the valine and arginine residue at the position 39 and 210 were significantly different from the wild type.
Conclusions: We have identified two novel heterozygous missense mutations in HOMEZ gene exon-2 in isolated VSD patients in the Chinese population and have found that these two mutations resulted in alteration of the hydropathicity of the HOMEZ protein. Therefore, the two missense mutations of the HOMEZ gene are directly linked with the etiology of isolated VSD in the Chinese population.