Novel Point Mutations of CITED2 Gene Are Associated with Non-familial Congenital Heart Disease (CHD) in Sporadic Pediatric Patients
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CITED2 is a cardiac transcription factor that plays a critical role in cardiac development. Gene mutations in CITED2 lead to a series of cardiac malformations and congenital heart defects (CHD). Congenital heart disease generally refers to defects in the heart’s structure or function and often seen in many forms such as ventricular septal defects (VSDs), atrial septal defects (ASDs), and tetralogy of Fallot (TOF). However, the mechanisms involved in these mutations are poorly understood. The aim of the present study was to evaluate the mutations of the CITED2 gene in pediatric patients with congenital heart defects. We studied the potential impact of sequence variations of the CITED2 gene in a cohort of 150 patients with non-familial CHD and 98 control individuals by polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) and subsequently direct sequencing. We identified seven novel CITED2 nucleotide changes. Four of these alterations were found in the coding region (c.716insG, c.389A>G, c.450G>C and c.512-538del27) and were only seen in our patients, and not detected in the control group. These mutations are leading to changes in the amino acid sequence in the position of p.Gly236fs, p.Asn125Ser, p.Gln145His, and p.Ser170-Gly178del, respectively. Other variations are located in the 5′UTR region of the gene (c.-43C>T, c.-64C>T and c.-90A>G). CITED2 gene mutations in control subjects were not observed. Our Bioinformatics assay results showed that these novel mutations alter the RNA folding, protein structure, and, therefore, probable effect on the protein function and may play a significant role in the development of congenital heart diseases.
KeywordsCongenital heart disease CITED2 Mutation PCR-SSCP
We thank all the patients for providing blood samples for scientific research, including the Afshar cardiac hospital patients (Yazd, Iran). The study was approved by the Yazd University Human Research Ethics Committee.
M.K. and M.M.H. conceived the study, participated in its design, and drafted the initial manuscript. M.M. and S.D. collected the data. M.K., M.M.H., Y.A.A, and S.D. performed statistics and interpretation of data and drafted the last version of the manuscript. M.K., M.M.H., and M.H. coordinated data interpretation, participated in the design of the study, and helped to draft the manuscript. All authors read and approved the final manuscript.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
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