THE PROBLEMS OF RETT SYNDROME DIAGNOSIS IN GIRLS WITHOUT A MUTATION IN THE MEСP2 GENE: APPLICATION OF MOLECULAR KARYOTYPING

Introduction. Rett syndrome (RTT) is the most common genetic syndrome underlying mental retardation and autism in girls. Etiology of this disorder is related to mutation in the MECP2 gene. However, there are many cases of this disease without the MECP2 mutations. The aim of the study. The aim of the study was the search of chromosomal microabnormalities and the number of copies of variations in RTT girls without point mutations in the MECP2 mutations.Methods. Using molecular karyotyping on DNA microarrays (array CGH) we have performed molecular cytogenetic analysis of microanomalies and genetic variations in 25 girls with a clinical diagnosis of Rett syndrome, but without point mutations in the MECP2 gene. Results. In 5 girls with some clinical manifestations of the disease microdeletions in Xq28 affecting the gene MECP2 were found. We propose that microdeletions in the area Xq28 affecting of the MECP2 gene produce a special subtype of RTT, which manifests clinically as milder form compared to the classical form of this monogenic syndrome. In one case, an atypical form of RTT has been associated with the genomic abnormalities affecting CDKL5 gene and microdeletions in critical region (15q11.2) of Prader-Willi and Angelman syndromes. In addition, data are presented for the first time that the variation in the genome regions 3p13 (one case), 3q27.1 (one case) and 1q21.1-1q21.2 (two cases) can produce RTT-like phenotype. It was proposed that these regions of the genome may contain new genes related etiologically to RTT-like phenotype. In 15 cases analyzed no pathologically significant variations in the genome have been identified. Conclusion. According to the findings absence of mutations in MECP2 gene in girls with mental retardation and autism, identified by the molecular genetic testing, is not an exclusion criteria for the clinical diagnosis of RTT. To avoid errors in the diagnosis of RTT a comprehensive genetic diagnosis involving molecular cytogenetic methods (array CGH or molecular karyotyping) is required.