[Causes and Consequences of Genome Instability in Psychiatric and Neurodegenerative Diseases].

Each neuron has 100-10000 connections (synapses) with other neural cells, therefore genome pathologies affecting a small proportion of brain cells are capable of causing dysfunction of the entire central nervous system (CNS). Recently, genome and chromosome instability has been uncovered in neurodegeneration (Alzheimer's disease, ataxia telangiectasia). Somatic tissue-specific mosaicism was observed in the brain of individuals with neuropsychiatric diseases including schizophrenia, autism, intellectual disability, and epilepsy. The study of genetic processes in neurons allows determination of a certain number of genetic pathways and candidate processes, modifications of which can cause impaired genome stability. Brain-specific somatic mutations generally occur at the earliest stages of development. Accordingly, genome variability and somatic mosaicism are expected to be mediated by cell cycle regulation, DNA repair, DNA replication, and programmed cell death in the brain. Endomitosis, endoreduplication, and abortive entrance to the cell cycle are also commonly observed in neurodegeneration. Brain-specific genome instability maybe a key element in the pathogenic cascade of neurodegeneration. Here we review the current state of knowledge concerning somatic genome variations in neurodegenerative and psychiatric diseases and analyze the causes and consequences of genomic instability in the CNS.

[Epigenomic variations manifesting as a loss of heterozygosity affecting imprinted genes represent a molecular mechanism of autism spectrum disorders and intellectual disability in children]. / Épigenomnye variatsii v vide poteri geterozigotnosti, zatragivaiushchei imprintirovannye geny, kak molekuliarnyi mekhanizm rasstroistv autisticheskogo spektra i umstvennoi otstalosti u detei.

AIM: Long continuous stretches of homozygosity (LCSH) are regularly detected in studies using molecular karyotyping (SNP array). Despite this type of variation being able to provide meaningful data on the parents' kinship, uniparental disomy and chromosome rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Despite their direct relationship to imprinting, LCSH in imprinted loci have not been considered in terms of pathogenicity. The present work is aimed at studying LCSH in chromosomal regions containing imprinted genes previously associated with disease in children with idiopathic intellectual disability, autism, congenital malformations and/or epilepsy. MATERIAL AND METHODS: Five hundred and four patients with autism spectrum disorders and intellectual disability were examined. RESULTS: LCSH affecting imprinted loci associated with various diseases were identified in 40 (7.9%) individuals. Chromosomal region 7q21.3 was affected in twenty three cases, 15q11.2 in twelve, 11p15.5 in five, 7q32.2 in four. Four patients had 2 LCSH affecting imprinted loci. Besides one LCSH in 7q31.33q32.3 (~4 Mbp) region, all LCSH were 1-1.6 Mbp. Clinically, these cases resembled the corresponding imprinting diseases (e.g. Silver-Russell, Beckwith-Wiedemann, Prader-Willi, Angelman syndromes). Parental kinship was identified in 8 cases (1.59%), which were not affected by LCSH at imprinted loci. CONCLUSION: The present study shows that LCSH affecting chromosomal regions 7q21.3, 7q32.2, 11p15.5 and 15p11.2 occur in about 7.9% of children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations is obviously common in a group of children with neurodevelopmental disorders. LCSH less than 2.5-10 Mbp are usually ignored in molecular karyotyping (SNP array) studies and, therefore, an important epigenetic cause of intellectual disability, autism or epilepsy with high probability remains without attention.

[Structural variations of the genome in autistic spectrum disorders with intellectual disability]. / Strukturnye variatsii genoma pri autisticheskikh rasstroistvakh s umstvennoi otstalost'yu.

AIM: To analyze structural variations in the genome in children with autism and intellectual disability. MATERIAL AND METHODS: Using high-resolution karyotyping (AffymetrixCytoScan HD Array) and original bioinformatic technology, 200 children with autism and intellectual disability were studied. RESULTS AND CONCLUSION: Data on structural variations in the genome in children with autism and intellectual disability are provided. Causative genomic pathology (chromosome abnormalities and copy number variations - CNV) was determined in 97 cases (48.5%). Based on these RESULTS: 24 candidate genes for autism with intellectual disability were selected. In 16 cases (8%), the chromosome mosaicism manifested as aneuploidy of whole autosomes and sex chromosomes (gonosomes) was identified. In 87 children (43.5%), there were genomic variations, which are characteristic of the so-called «grey zone¼ of genetic pathology in mental illnesses. Bioinformatic analysis showed that these genomic variations had a pleiotropic effect on the phenotype.

[Subchromosomal microdeletion identified by molecular karyotyping using DNA microarrays (array CGH) in Rett syndrome girls negative for MECP2 gene mutations].

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.

[Genomic abnormalities in children with mental retardation and autism: the use of comparative genomic hybridization in situ (HRCGH) and molecular karyotyping with DNA-microchips (array CGH)].

Genomic abnormalities occur with high frequency in children with mental retardation and autistic spectrum disorders (ADS). Molecular karyotyping using DNA microarrays is a new technology for diagnosis of genomic and chromosomal abnormalities in autism implemented in the fields of biological psychiatry and medical genetics. We carried out a comparative analysis of the frequency and spectrum of genome abnormalities in children with mental retardation and autism of unknown etiology using high-resolution comparative genomic methods for hybridization (HRCGH) and molecular karyotyping (array CGH). In a study of 100 children with autism, learning difficulties and congenital malformations by HRCGH, we identified genomic rearrangements in 46% of cases. Using array CGH we examined 50 children with autism. In 44 cases out of 50 (88%), different genomic abnormalities and genomic variations (CNV - copy number variations) were identified. Unbalanced genomic rearrangements, including deletions and duplications, were found in 23 cases out of 44 (52%). These data suggest that genomic abnormalities which are not detectable by common methods of chromosome analysis are often discovered by molecular cytogenetic techniques in children autism spectrum disorders. In addition, 54 children with idiopathic mental retardation and congenital malformations (31 boys and 23 girls) without autism spectrum disorders were examined using molecular karyotyping and microarray containing an increased number of DNA samples for genomic loci of chromosome X. Deletions and duplications affecting different regions of the chromosome X were detected in 11 out of 54 children (20.4%).

[Chromosomal mosaicism in spontaneous abortions: analysis of 650 cases].

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.

[Cytogenetic, molecular cytogenetic, clinical and genealogical study of mothers of children with autism: a search for family genetic markers of autistic disorders].

Using modern cytogenetic and molecular cytogenetic techniques towards the study of human chromosomes, an analysis of chromosomal abnormalities/chromosomal variations as well as clinical and genealogical data in mothers of children with autism has been performed. It has been shown that mothers of autistic children exhibit an increased incidence of chromosomal abnormalities (mainly mosaic forms involving chromosome X) and an increased occurrence of chromosomal variations compared to controls. The analysis of genotype-phenotype correlations revealed the increase in the frequency of cognitive disturbances and spontaneous abortions in mothers of children with autism as well as the higher frequency of mental retardation, early death and reproductive problems in the pedigrees. The high frequency of congenital malformations in the pedigrees of mothers with chromosomal variations was observed as well. Taking into account the data obtained, we have concluded that cytogenetic and molecular cytogenetic studies of mothers of children with autism are obligatory for detection of possible genetic causes of autism and genetic counseling of families with children affected with autistic disorders.