| Abstract [eng] |
Despite numerous genome-wide studies that have already been performed, the clinical significance of most of coding and non-coding DNA sequence variants and copy number variants (CNVs) is unknown or still unconfirmed. In this study, previously undescribed novel DNA sequence splicing variants and CNVs, which cause intellectual disability and / or congenital anomalies (ID / CA), have been selected for a molecular and functional characterization at the mRNA level. The analysis of cDNA confirmed the pathogenicity of splice site variants, the unique consequences of which were revealed at the protein level via in silico analysis. The investigation of CNVs provided the information about the origin, size, and gene content of the chromosomal alteration, thus allowing to identify a new syndrome, to narrow the critical regions of known syndromes, or even to identify the critical genes for syndromes. In order to confirm the pathogenicity of a genetic variant, for the first time, the novel CRISPR-Cas9 technology was used for the MED13L gene silencing experiment in the fibroblasts culture. These molecular and functional genomic approaches provide an unique possibility to understand the etiopathogenetic mechanisms of many diseases and conditions, including ID/CA. The expansion of the scientific knowledge and molecular diagnostic capability may contribute for the development of a novel diagnostic and therapeutic strategies in the future. |
