I A Demidova

Russian Academy of Medical Sciences, Moskva, Moscow, Russia

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Publications (34)38.13 Total impact

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    ABSTRACT: We examined 30 patients with a presumptive diagnosis of Prader-Willi and Angelman syndromes. In four patients, 15q11.2-q13 deletions were identified by cytogenetic techniques. The FISH method was used to study eight patients, in five of them microdeletions were also confirmed. High-resolution comparative genomic hybridization (CGH) and comparative genomic hybridization using DNA microarrays (array CGH) allowed to find 15q11.2-q13 deletions in five patients. These cases demonstrate the need for high-resolution post-genomic technologies (array CGH - molecular karyotyping) in the combination with classical cytogenetic and molecular cytogenetic techniques.
    Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoi promyshlennosti Rossiiskoi Federatsii, Vserossiiskoe obshchestvo nevrologov [i] Vserossiiskoe obshchestvo psikhiatrov 01/2014; 114(1):49-53. · 0.05 Impact Factor
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    ABSTRACT: Rett syndrome (RTT) is an X-linked neurodevelopmental disease affecting predominantly females caused by MECP2 mutations. Although RTT is classically considered a monogenic disease, a stable proportion of patients, who do not exhibit MECP2 sequence variations, does exist. Here, we have attempted at uncovering genetic causes underlying the disorder in mutation-negative cases by whole genome analysis using array comparative genomic hybridization (CGH) and a bioinformatic approach. Using BAC and oligonucleotide array CGH, 39 patients from RTT Russian cohort (in total, 354 RTT patients), who did not bear intragenic MECP2 mutations, were studied. Among the individuals studied, 12 patients were those with classic RTT and 27 were those with atypical RTT. We have detected five 99.4 kb deletions in chromosome Xq28 affecting MECP2 associated with mild manifestations of classic RTT and five deletions encompassing MECP2 spanning 502.428 kb (three cases), 539.545 kb (one case) and 877.444 kb (one case) associated with mild atypical RTT. A case has demonstrated somatic mosaicism. Regardless of RTT type and deletion size, all the cases exhibited mild phenotypes. Our data indicate for the first time that no fewer than 25% of RTT cases without detectable MECP2 mutations are caused by Xq28 microdeletions. Furthermore, Xq28 (MECP2) deletions are likely to cause mild subtypes of the disease, which can manifest as both classical and atypical RTT.
    Molecular Cytogenetics 11/2013; 6(1):53. · 2.66 Impact Factor
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    ABSTRACT: Molecular karyotyping using DNA microarrays (array CGH) was applied for identification of subchromosomal microdeletions in a cohort of 12 girls with clinical features of RETT syndrome, but negative for MECP2 gene mutations. Recurrent microdeletions of MECP2 gene in chromosome X (locus Xq28) were identified in 5 girls of 12 studied. Probably RTT girls with subchromosomic microdeletions in Xq28 could represent a special subtype of the disease, which appears as clinically milder than the classic form of disease. In one case, an atypical form of RTT was associated with genomic abnormalities affecting CDKL5 gene and region critical for microdeletion Prader-Willi and Angelman syndromes (15q11.2). In addition, data are presented for the first time that genetic variation in regions 3p13, 3q27.1, and 1q21.1-1q21.2 could associate with RTT-like clinical manifestations. Without application of molecular karyotyping technology and bioinformatic method of assessing the pathogenic significance of genomic rearrangements these RTT-like girls negative for MECP2 gene mutations were considered as cases of idiopathic mental retardation associated with autism. It should be noted that absence of intragenic mutations in MECP2 gene is not sufficient criteria to reject the clinical diagnosis of RTT. To avoid errors in the genetic diagnosis of this genetically heterogeneous brain disease molecular cytogenetic studies using high resolution oligonucleotide array CGH (molecular karyotyping) are needed.
    Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoi promyshlennosti Rossiiskoi Federatsii, Vserossiiskoe obshchestvo nevrologov [i] Vserossiiskoe obshchestvo psikhiatrov 01/2013; 113(10):63-68. · 0.05 Impact Factor
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    ABSTRACT: It is known that up to 50% spontaneous abortions (SA) in the first trimester of pregnancy are associated with chromosomal abnormalities. We studied mosaic forms of chromosomal abnormalities in 650 SA specimens using interphase mFISH and DNAprobes for chromosomes 1,9, 13/21, 14/22, 15, 16, 18, X, and Y. Numerical chromosomal abnormalities were discovered in 58.2% (378 cases). They contained combined chromosomal abnormalities (aneuploidy of several chromosomes or aneuploidy in combination with polyploidy in the same specimen) in 7.7% (29 cases) or 4.5% of the entire SA sample; autosomal trisomy, in 45% (18.2% in chromosome 16, 8.9% in chromosomes 14/22, 7.9% in chromosomes 13/21, 3.1% in chromosome 18, and 1.4% in chromosome 9). Chromosome X aneuploidy was found in 27% cases, among which 9.6% represented chromosome X monosomy. Polyploidy was observed in 22.9% cases. In 5.1% cases, we observed mosaic form of autosomal monosomy Among the SA cases with chromosomal abnormalities mosaicism was observed in 50.3% (approximately 25% of the entire SA sample). The results of the present study indicate that significant amount of chromosomal abnormalities in SA cells are associated with disturbances in mitotic chromosome separation, which represents the most common cause of intrauterine fetal death. It was also shown that original collection of DNA probes and the technique of interphase MFISH could be useful for detection of chromosomal mosaicism in prenatal cell specimens.
    Genetika 10/2010; 46(10):1356-9. · 0.37 Impact Factor
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    ABSTRACT: State-of-the-art cytogenetic and molecular-cytogenetic methods for studying human chromosomes were used to analyze chromosomal anomalies and variants in mothers of children with autistic disorders and the results were compared with clinical-genealogical data. These investigations showed that these mothers, as compared with a control group, showed increases in the frequencies of chromosomal anomalies (mainly mosaic forms involving chromosome X) and chromosomal heteromorphisms. Analysis of correlations of genotypes and phenotypes revealed increases in the frequencies of cognitive impairments and spontaneous abortions in the mothers of children with autism with chromosomal anomalies, as well as increases in the frequencies of mental retardation, death in childhood, and impairments to reproductive function in the pedigrees of these women. There was a high incidence of developmental anomalies in the pedigrees of mothers with chromosomal variants. These results lead to the conclusion that cytogenetic and molecular-cytogenetic studies of mothers and children with autism should be regarded as obligatory in terms of detecting possible genetic causes of autism and for genetic counseling of families with autistic children.
    Neuroscience and Behavioral Physiology 09/2010; 40(7):745-56.
  • Reproductive biomedicine online 05/2010; 20. · 2.98 Impact Factor
  • Reproductive biomedicine online 05/2010; 20. · 2.98 Impact Factor
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    ABSTRACT: It is known that up to 50% spontaneous abortions (SA) in the first trimester of pregnancy are associated with chromosomal abnormalities. We studied mosaic forms of chromosomal abnormalities in 650 SA specimens using interphase MFISH and DNA probes for chromosomes 1, 9, 13/21, 14/22, 15, 16, 18, X, and Y. Numerical chromosomal abnormalities were discovered in 58.2% (378 cases). They contained combined chromosomal abnormalities (aneuploidy of several chromosomes or aneuploidy in combination with polyploidy in the same specimen) in 7.7% (29 cases) or 4.5% of the entire SA sample; autosomal trisomy, in 45% (18.2% in chromosome 16, 8.9% in chromosomes 14/22, 7.9% in chromosomes 13/21, 3.1% in chromosome 18, and 1.4% in chromosome 9). Chromosome X aneuploidy was found in 27% cases, among which 9.6% represented chromosome X monosomy. Polyploidy was observed in 22.9% cases. In 5.1% cases, we observed mosaic form of autosomal monosomy. Among the SA cases with chromosomal abnormalities mosaicism was observed in 50.3% (∼ 25% of the entire SA sample). The results of the present study indicate that significant amount of chromosomal abnormalities in SA cells are associated with disturbances in mitotic chromosome separation, which represents the most common cause of intrauterine fetal death. It was also shown that original collection of DNA probes and the technique of interphase MFISH could be useful for detection of chromosomal mosaicism in prenatal cell specimens.
    Russian Journal of Genetics 01/2010; 46(10):1197-1200. · 0.41 Impact Factor
  • International Journal of Psychophysiology 09/2008; 69(3):241-241. · 2.65 Impact Factor
  • International Journal of Psychophysiology 09/2008; 69(3):288-289. · 2.65 Impact Factor
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    ABSTRACT: Genetic instability manifested as loss or gain of whole chromosomes (aneuploidy) is a newly described feature of the human brain. Aneuploidy in the brain was hypothesized to be involved in schizophrenia pathogenesis. To gain further insights into the relationship between aneuploidy in the brain and schizophrenia pathogenesis, a molecular-cytogenetic study of chromosome 1 aneuploidy was performed. Interphase multiprobe fluorescence in situ hybridization (FISH) with quantitative FISH (QFISH) and interphase chromosome-specific multicolor banding (ICS-MCB) were used to define aneuploidy rate in 12 unaffected and 12 schizophrenia brains. In the unaffected brain (n=12; 22,794 cells analyzed), average frequencies of stochastic chromosome 1 loss and gain were 0.3% (95%CI 0.2-0.4%) and 0.3% (95%CI 0.2-0.4%), respectively. The threshold level for stochastic chromosome gain and loss (the mean+3SD) in the normal brain was 0.7%. Average rate of aneuploidy in the schizophrenia brain (n=12; 28,482 cells analyzed) was 0.9% (95%CI 0.3-1.5%) for chromosome 1 loss and 0.9% (95%CI 0.2-1.7%) for chromosome 1 gain. Significantly increased level of mosaic aneuploidy involving chromosome 1 was revealed in two schizophrenia brains (3.6% and 4.7% of cells with chromosome 1 loss and gain, respectively). Stochastic aneuploidy rate for chromosome 1 in the schizophrenia brain without two outliers (n=10) reached 0.6% (95%CI 0.3-0.9%) for loss and 0.5% (0.2-0.9%) for gain and was higher than in controls (P=0.005 and P=0.001, respectively). Our findings support the hypothesis suggesting that subtle genomic imbalances manifesting as low-level mosaic aneuploidy may contribute to schizophrenia pathogenesis.
    Schizophrenia Research 02/2008; 98(1-3):139-47. · 4.43 Impact Factor
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    ABSTRACT: Autism is a common childhood neurodevelopmental disorder with a possible genetic background. About 5-10% of autism cases are associated with chromosomal abnormalities or monogenic disorders. However, the role of subtle genomic imbalances in autism has not been delineated. This study aimed to investigate a hypothesis suggesting autism to be associated with subtle genomic imbalances presenting as low-level chromosomal mosaicism. We surveyed stochastic (background) aneuploidy in children with/without autism by interphase three-colour fluorescence in situ hybridisation. The rate of chromosome loss and gain involving six arbitrarily selected autosomes and the sex chromosomes was assessed in the peripheral blood cells of 60 unaffected children and 120 children with autism. Of 120 analysed boys with autism, 4 (3.3%) with rare structural chromosomal abnormalities (46,XY,t(1;6)(q42.1;q27); 46,XY,inv(2)(p11q13); 46,XY,der(6),ins(6;1)(q21;p13.3p22,1)pat; and 46,XY,r(22)(p11q13)) were excluded from further molecular cytogenetic analysis. Studying <420 000 cells in 60 controls and 116 children with idiopathic autism, we determined the mean frequency of stochastic aneuploidy in control and autism: (1) autosome loss 0.58% (95% CI 0.42 to 0.75%) and 0.60% (95% CI 0.37 to 0.83%), respectively, p = 0.83; (2) autosome gain 0.15% (95% CI 0.09 to 0.21%) and 0.22% (95% CI 0.14 to 0.30%), respectively, p = 0.39; and (3) chromosome X gain 1.11% (95% CI 0.90 to 1.31%) and 1.01% (95% CI 0.85 to 1.17%), respectively, p = 0.30. A frequency of mosaic aneuploidy greater the background level was found in 19 (16%) of 116 children with idiopathic autism, whereas outlier values were not found in controls (p = 0.0019). Our findings identify low-level aneuploidy as a new genetic risk factor for autism. Therefore, molecular cytogenetic analysis of somatic mosaicism is warranted in children with unexplained autism.
    Journal of Medical Genetics 09/2007; 44(8):521-5. · 5.64 Impact Factor
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    ABSTRACT: Cytogenetic and molecular cytogenetic analysis of children with autism (90 subjects) and their mothers (18 subjects) is presented. Anomalies and fragility were found in chromosome X in four cases of autism: mos 47,XXX[98]/46, XX[2]; 46,XY,r(22)(p11q13); 46,XY,inv(2)(p11.2q13),16qh-; and 46,Y,fra(X)(q27.3),16qh-. C staining and quantitative fluorescent in situ hybridization (FISH) were used to demonstrate a significant increase in the frequency of variations in the heterochromatin regions of chromosomes in children with autism as compared with a control group (48% and 16% respectively). Pericentric chromosome inversion 9phqh was not characteristic of patients with autism, while variation in heterochromatin regions 1phqh, 9qh+, and 16qh-were found significantly more frequently in children with autism. These data provide the basis for discussing the possible role of the gene position effect in the pathogenesis of autism and the possible search for biological markers of autistic disorders.
    Neuroscience and Behavioral Physiology 08/2007; 37(6):553-8.
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    ABSTRACT: Understanding the mechanisms underlying generation of neuronal variability and complexity remains the central challenge for neuroscience. Structural variation in the neuronal genome is likely to be one important mechanism for neuronal diversity and brain diseases. Large-scale genomic variations due to loss or gain of whole chromosomes (aneuploidy) have been described in cells of the normal and diseased human brain, which are generated from neural stem cells during intrauterine period of life. However, the incidence of aneuploidy in the developing human brain and its impact on the brain development and function are obscure. To address genomic variation during development we surveyed aneuploidy/polyploidy in the human fetal tissues by advanced molecular-cytogenetic techniques at the single-cell level. Here we show that the human developing brain has mosaic nature, being composed of euploid and aneuploid neural cells. Studying over 600,000 neural cells, we have determined the average aneuploidy frequency as 1.25-1.45% per chromosome, with the overall percentage of aneuploidy tending to approach 30-35%. Furthermore, we found that mosaic aneuploidy can be exclusively confined to the brain. Our data indicates aneuploidization to be an additional pathological mechanism for neuronal genome diversification. These findings highlight the involvement of aneuploidy in the human brain development and suggest an unexpected link between developmental chromosomal instability, intercellural/intertissular genome diversity and human brain diseases.
    PLoS ONE 02/2007; 2(6):e558. · 3.53 Impact Factor
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    ABSTRACT: We report on a case of chimerism and multiple abnormalities of chromosomes 21, Xand Yin spontaneous abortion specimen. To the best our knowledge the present case is the first documented chimera in a spontaneously aborted fetus. The application of interphase fluorescence in situ hybridization (FISH) using chromosome enumeration and site-specific DNA probes showed trisomy X in 92 nuclei (23 %), tetrasomy X in 100 nuclei (25 %), pentasomy of chromosome X in 40 nuclei (10 %), XXY in 36 nuclei (9 %), XXXXXXYY in 12 nuclei (3 %), XXXXXYYYYY in 8 nuclei (2 %), trisomy 21 and female chromosome complement in 40 nuclei (10 %), normal female chromosome complement in 72 nuclei (18 %) out of 400 nuclei scored. Our experience indicates that the frequency of chimerism coupled with multiple chromosome abnormalities should be no less than 1 : 400 among spontaneous abortions. The difficulties of chimerism identification in fetal tissues are discussed.
    T͡Sitologii͡a i genetika 01/2006; 40(5):28-30.
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    ABSTRACT: In the present study, the cytogenetic and molecular cytogenetic analysis of 90 children with autism and their mothers (18 subjects) was carried out. Chromosome fragility and abnormalities were found in four cases: mos 47,XXX[98]/ 46,XX[2]; 46,XY,r(22)(p11q13); 46,XY,inv(2)(p11.2q13),16qh-; 46Y,fra(X)(q27.3)16qh-. Using C-banding and quantitative fluorescent in situ hybridization (FISH), the significantly increased incidence of heterochromatic region variation was shown in autism as compared to the controls (48 and 16%, respectively). Pericentric 9phqh inversion was not characteristic of the patients with autism whereas heterochromatic variations 1phqh, 9qh+ and 16qh- were more frequent in autism (p<0,05). Basing on the data obtained, a possible role of position effect in autism pathogenesis as well as a potential of heterochromatic region variation analysis for the search of biological markers of autistic spectrum disorders are discussed.
    Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoi promyshlennosti Rossiiskoi Federatsii, Vserossiiskoe obshchestvo nevrologov [i] Vserossiiskoe obshchestvo psikhiatrov 01/2006; 106(6):52-7. · 0.05 Impact Factor
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    ABSTRACT: Rett's syndrome (RTT) is a severe hereditary disorder of the nervous system. MECP2 gene mutations are considered as a primary cause of the disease. In the present study, we have found MECP2 mutations in 33 (84.6%) out of 39 RTT females. We have also studied X-inactivation patterns in 70 girls with RTT. A frequency of skewed X-inactivation was 37% (26 patients), being significantly higher (p < 0.001) than that in the controls. The investigation of inactivated X chromosome origin revealed that about 33% pairs had preferentially the inactivated maternal X chromosome. An abnormal type of chromosome X inactivation was observed in all RTT females. Thus, we conclude that skewed X-inactivation may be considered as a common feature of RTT. There is unambiguous evidence that epigenetic alterations in RTT are associated with MECP2 mutations. MeCP2 protein also appears to be involved in transcriptional regulation of chromosome X genes. RTT in females without MECP2 mutations is related to the epigenetic alterations. We suggest X chromosome inactivation study in RTT females and their mothers to be informative for investigation of genetic processes in RTT girls, even in case MECP2 mutations have not been found. RTT could be considered as an appropriate model for studying epigenetic abnormalities in relation to autistic spectrum disorders.
    Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoi promyshlennosti Rossiiskoi Federatsii, Vserossiiskoe obshchestvo nevrologov [i] Vserossiiskoe obshchestvo psikhiatrov 02/2005; 105(7):4-11. · 0.05 Impact Factor
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    ABSTRACT: The analysis of non-disjunction of chromosome 21 and alphoid DNA variation by using cytogenetic and molecular cytogenetic techniques (quantitative fluorescence in situ hybridization) in 74 nuclear families was performed. The establishment of possible correlation between alphoid DNA variation, parental age, environmental effects, and non-disjunction of chromosome 21 was made. The efficiency of techniques applied was found to be 92% (68 from 74 cases). Maternal non-disjunction wasfound in 58 cases (86%) and paternal non-disjunction - in 7 cases (10%). Post-zygotic mitotic non-disjunction was determined in 2 cases (3%) and one case was associated with Robertsonian translocation 46,XX,der(21;21)(q10;q10), +21. Maternal meiosis I errors were found in 43 cases (64%) and maternal meiosis II errors--in 15 cases (22%). Paternal meiosis I errors occurred in 2 cases (3%) and paternal meiosis I errors--in 5 cases (7%). The lack of the correlation between alphoid DNA variation and non-disjunction of chromosome 21 was established. Sociogenetic analysis revealed the association of intensive drug therapy of infectious diseases during the periconceptual period and maternal meiotic non-disjunction of chromosome 21. The correlation between non-disjunction of chromosome 21 and increased parental age as well as exposure to irradiation, alcohol, tobacco, mutagenic substances was not found. The possible relevance of data obtained to the subsequent studies of chromosome 21 non-disjunction is discussed.
    T͡Sitologii͡a i genetika 01/2005; 39(6):30-6.
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    ABSTRACT: Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 gene (MECP2). We carried out a mutations analysis in Russian cohort of patients with RTT. MECP2 mutations were found in 23 of 28 RTT girls and one boy (82%). Thirteen different types of mutations have been identified: 6 nonsense, 5 missense and 2 deletions in MECP2 gene. In typical RTT form, most frequent mutations were R255X (5 cases) and T158M (4 cases). A boy with classical clinical picture of RTT had R270X mutation. Skewed inactivation of chromosome x has been found in 2 of 27 RTT girls with classical RTT form and "forme fruste". The data obtained imply possible correlations between genotype and phenotype in RTT.
    Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoi promyshlennosti Rossiiskoi Federatsii, Vserossiiskoe obshchestvo nevrologov [i] Vserossiiskoe obshchestvo psikhiatrov 02/2002; 102(10):23-9. · 0.05 Impact Factor
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    ABSTRACT: Rett syndrome (RTT) is a severe neurodevelopmental disorder with an incidence of 2.5% in mentally retarded girls in Russia. We have performed cytogenetic studies of 60 patients (57 girls and three boys) with a clinical picture of RTT, selected according to the criteria for diagnosis of RTT defined by B. Hagberg et al. in 1996. Collection of DNA samples and fixed cell suspensions of RTT patients (37 girls and two boys) and their parents (27 patients) was established for molecular studies, for example analysis of MECP2 mutations in a Russian cohort of RTT patients. Among 60 patients 57 girls with a clinical picture of RTT had normal female karyotype (46,XX), one boy had normal male karyotype in peripheral lymphocytes (46,XY) and two boys had a mosaic form of Kleinfelter's syndrome (47,XXY/46,XY) in peripheral lymphocytes or muscle cells (with MeCP2 mutation R270X). Twenty-four mothers and parents of RTT girls had normal karyotype, two mothers had mosaic forms of Turner syndrome (45,X/46,XX) and one had mosaic karyotype (47,XX,+mar/48,XXX,+mar). We analyzed chromosome X in lymphocytes of 57 affected girls with a clinical picture of RTT using the 5-bromo-2′-deoxyuridine+Giemsa staining technique. A specific type of inactive chromosome X (so-called type ‘C’) with unusual staining of chromatin in the long arm of chromosome X was found in 55 (from 57) girls with RTT. This technique was positively used for presymptomatic diagnosis of RTT in five girls in earlier stages of the disease. We believe that the phenomenon of altered chromatin conformation in inactive chromosome X could be used as a laboratory test for preclinical diagnosis of the RTT.
    Brain and Development 01/2002; · 1.54 Impact Factor