DOI: 10.18413/2658-6533-2020-6-2-0-3

Molecular karyotyping of chromosomal anomalies and copy number variations (CNVs) in idiopathic forms of intellectual disability and epilepsy

Background: Genetic factors play an important role in the etiology of idiopathic intellectual disability and epilepsy. The intensive introduction of molecular cytogenetic technologies in medical practice has made it possible to reveal genomic rearrangements at a previously unachievable level of resolution. However, in spite of profound progress in learning genetic causes of intellectual disability, it is necessary to use bioinformatic (interpretational) technologies for correct interpretation of the personal data during the examination of a genome. The aim of the study: To determine genomic (chromosomal) variations, including CNVs, and their possible clinical consequences in children with idiopathic intellectual disability and epilepsy. Materials and methods: We examined blood cells and DNA samples of 294 children with idiopathic intellectual disability and epilepsy, congenital malformations and/or microanomalies. We used methods of high-resolution molecular karyotyping (SNP array), and an original bioinformatic technology for modeling consequences of genomic pathologies. Results: We examined 294 children with genomic anomalies and different phenotypic manifestations. In 20.8% of cases they had epilepsy, besides idiopathic intellectual disability, congenital malformations and/or microanomalies. Cytogenetic studies of these children revealed structural and numerical anomalies of chromosomes in 8% of cases. Molecular karyotyping revealed 192 genome anomalies with pathogenic or possibly pathogenic effect in 61 children and 23 regions of segmental loss of heterozygosity (segmental uniparental disomy) in 25% of cases. Combined genome anomalies were found in 87% of cases. Genomic anomalies were revealed in all chromosomes, except chromosomes 20 and 21. Among 192 genome anomalies we found deletions, duplications, triplications and mosaic genome aberrations, usually in combination with regular rearrangements. Using original bioinformatic analysis with gene prioritization, we defined more than 800 genes; recurrently affected genes were FMR1 [OMIM:309550] (this gene is associated with fragile X mental retardation), DAZ2 [OMIM:400026], DAZ3 [OMIM:400027] (both are associated with intellectual disability and autism), BTRC [OMIM:603482] (the gene is involved in signal pathway of circadian rhythm, associated with epileptic manifestations); less frequently – AFF2 (FMR2) [OMIM:300806], SLC1A1 [OMIM:133550], SCN2A [OMIM:182390], SCN3A [OMIM:182391], GABRB3 [OMIM:137192], NECAP1 [OMIM:615833], SHANK3 [OMIM:606230]. The variability of obtained data hinders exact phenotypic correlations of genomic disbalances and idiopathic intellectual disability with epilepsy. Nevertheless, the results of the studies show a need to accumulate whole-genome data for definition of genome sites or even genes, associated with this pathology. Conclusion: Our data and analysis highlight the applicability of the approach for identification of molecular mechanisms of idiopathic intellectual disability and epilepsy.

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