Evaluation of Genomic Variants in Non-syndromic Congenital Heart Disease in Turkish Pediatric Group

Genomic Variants in Non-Syndromic Congenital Heart Disease

Abstract

Objective: Congenital heart disease (CHD) is the most common congenital malformation in the population, and so far, all the known genetic factors could explain only 20-25% of the cases.
Material and Methods: In this study, microarray analysis was performed, and next-generation sequencing of Myosin Heavy Chain 6 (MYH6), NK2 Homeobox 5 (NKX2-5), GATA Binding Protein 4 (GATA4), Notch Receptor 1 (NOTCH1), and T-Box Transcription Factor 1 (TBX1) genes, which are known to be involved in the etiology of non-syndromic CHD, was performed in 40 patients with isolated cardiac defects between the ages of 0-18 and 40 age-matched controls.
Results: In microarray analysis, 9 novel copy-number variations (CNVs) that were not reported in population databases, and included OMIM genes were detected in 1.5% (6/40) of the patients. Even though the detected CNVs had not been previously associated with CHDs and were classified as Variant of Uncertain Significance (VUS), overall CNV count burden in the patient group was significantly higher than in the control group. Also, there were no pathogenic/likely pathogenic sequence variants in MYH6, NKX2-5, GATA4, NOTCH1, and TBX1 genes. The c.700C>T [p.(Arg234Cys)] and c.5949C>G [p.(Asn1983Lys)] in the NOTCH1 gene were classified as VUS and have not been detected in the control group.
Conclusion: Although microarray technologies and candidate gene sequencing are useful diagnostic tools, routine genetic testing of sporadic non-syndromic CHD patients is controversial. We believe that still remains a challenge to interpret the variants detected in multifactorial CHD with complex etiology, and further studies are needed.