[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.

[Clinical and genetic characteristics of the X chromosome distal long arm microduplications encompassing the MECP2 gene].

OBJECTIVE: Microduplications of the long arm of the X chromosome including the MECP2 gene are relatively common causes of neurodevelopmental disorders in males. Authors analyzed clinical presentations of this disease in children. MATERIAL AND METHODS: Authors performed a clinical and genetic analysis of four cases using contemporary cytogenetic, molecular cytogenetic studies (FISH, array CGH) and X chromosome inactivation analysis. RESULTS AND CONCLUSION: We described somatic, neurologic and mental symptoms of the patients. The genetic imbalance impact on the patients' phenotype, necessity of comprehensive family studies for correct genetic diagnosis and effective genetic counseling in cases of microduplications of the long arm of the X chromosome including the MECP2 gene are discussed.

[The use of molecular cytogenetic and cytogenetic techniques for the diagnosis of Prader-Willi and Angelman syndrome].

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.

Cytogenetic, molecular-cytogenetic, and clinical-genealogical studies of the mothers of children with autism: a search for familial genetic markers for autistic disorders.

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.

Variability in the heterochromatin regions of the chromosomes and chromosomal anomalies in children with autism: identification of genetic markers of autistic spectrum disorders.

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.

Two new cases of the Christchurch (Ch1) chromosome 21: evidence for clinical consequences of de novo deletion 21P-.

We performed an investigation of two unrelated cases with extremal variants of chromosome 21 without visible materials of the short arms (Christchurch or Ch1 chromosome). In the first case chromosome 21p- was initially detected during routine cytogenetic amniocentesis. Chromosomal variant was inherited from phenotypically normal father to phenotypically normal fetus (phenotypically normal boy after the birth). The second case of chromosome 21p- was detected in 7 years old boy, referred to cytogenetic analysis due to mental retardation and mild congenital malformation, including prenatal hypoplasia, microcephaly, low-set dysplastic ears, short nose, micrognatia, short neck. Molecular characterization of 21p-variant chromosomes was performed by the use of FISH with DNA probes specific to the short arm and centromeric region of chromosome 21 (telomeric, beta-satellite, ribosomal, classical satellite and alphoid DNA probes). Chromosomes 21p-hybridized positively only with telomeric DNA at both chromosomal ends and alphoid DNA probes at centromeric region of the first patient. In second case (de novo deletion of 21p), the Ch1 was associated with clinical phenotype and loss of telomeric and subtelomeric DNA in the p-arm of chromosome 21. Therefore, the complete absent of the short arm of chromosome 21 may be considered as abnormal. We propose that de novo deletion 21p- could have negative consequences due to absence of large portion of chromosomal DNA from the p-arm (telomeric, satellite or ribosomal DNAs) and following imbalance in organization and functioning of genome.