| Abstract [eng] |
Congenital heart diseases (CHDs) are the most frequent congenital developmental anomalies in infancy, diagnosed to 8 out of 1000 liveborn infants. Some of CHDs have a poor prediction of survival and are among the major causes of non-infectious death in neonatancy. The etiology of a majority of CHDs is still unclear. The objective of the study is to determine and evaluate the importance of genomic variants and of candidate genes in etiopathogenesis of congenital heart diseases. This piece of research was carried out on 132 subjects with CHDs. Phenotypic heterogeneity and complexity is typical to CHDs. Single nucleotide polymorphism – comparative genomic hybridization genotyping was used and 44 (17.39 percent) pathogenic copy number variations (CNVs) were determined in the group of subjects. These results show that pathogenic CNVs are frequent causative variants in the genome in the etiology of syndromic CHDs and CHDs, manifesting themselves with other developmental anomalies and/or dysmorphic features. Prioritization of the genes, linked to molecular pathways and biological processes of heart development, the following 8 candidate genes of CHDs were determined – FGF9, BMPR1A, PTEN, ANKRD17, NPPA, LMNA, NFATC1 and IFT88. Five de novo deletions and one deletion of maternal origin encompassed aforementioned genes. This piece of research revealed that rare genetic CNVs (rare deletions and duplications) manifested themselves 2.65 times more frequently in the group of subjects with CHDs (p<0,0001), whereas large (of ≥501 kb) rare genetic CNVs were 6.63 times more significantly frequent in the subjects with CHDs than in the control group (p<0,0001). Rare CNVs included 2.45 times significantly more genes with a high degree of haploinsufficiency in the groups of subjects with CHDs than in the control group (p=0,0187). This suggests that rare genetic CNVs may possibly lead to a higher risk of CHDs. |
