Gulkovskyi R. Gene mutations in children with intellectual disability

Object - hereditary nature of intellectual disability in children. Aim - to clarify the role of EPHA1, PUS3, ZNF527, SCEL, C6orf223 genes mutations, identified by exome sequencing of two affected siblings with intellectual disability, and LIF gene polymorphism as genetic factors of ID pathogenesis. Methods - isolation and purification of genomic DNA, polymerase chain reaction, restriction fragment length polymorphism analysis, sequencing, bioinformatic modeling and statistical analysis. Results and their novelty - missense mutations c.1891G>A in exon 11 of the gene EPHA1 and c.212A> G in the 1st exon PUS3 gene were first identified. The data on distribution of EPHA1 gene c.1475G>A (rs11768549) and c.1891G>A (novel mutation), PUS3 gene c.212A>G (novel mutation) and ZNF527 gene c.806_808CAT > TGTGCA (rs386809049) allelic variants that we have identified in patients with intellectual disability in a population of Ukraine were first obtained. The homology models of wild type and mutant protein products of human PUS3 and EPHA1 genes were generated. The evidence in support the view that of с.1475G>A and с.1891G>A EPHA1 gene mutations being a genetic factors of monogenic intellectual disability were presented. Assays for the detection of EPHA1 gene с.1891G>A (novel) and с.1475G>A (rs11768549) mutations as well as EPHA1 gene rs11767557, rs11771145 and LIF gene rs929271 polymorphisms, suitable for genetic testing in groups with intellectual disability, were developed. It was established that carriage of EPHA1 gene 1475A and LIF gene 4524G (rs929271) alleles is a factor of genetic susceptibility to the intellectual disability development. It was shown that having the alleles 3022C (rs11767557) as well as 1399A (rs11771145) of EPHA1 gene has a protective effect and results in a significantly lower odds for intellectual disability development. Field - molecular genetics.