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Cryptic Rearrangements of Human Chromosomes Associated with Autism Spectrum Disorders
Křivánková, Anna ; Šolc, Roman (advisor) ; Růžičková, Šárka (referee)
Autism spectrum disorders (ASD) are heterogeneous group of neurodevelopmental disabilities characterized by antisociality and atypical behavioral patterns. Its etiology is very complex, autism is usually formed by combining many factors. One of the causes may be genetic (gene mutation). It is known about 450 candidate genes for ASD so far. Minority of these genes occur in loci which are affected by cryptic rearrangements. These rearrangements significantly contribute to manifestation of this disorder. Patologies they cause, lead to syndromes with high penetrance for ASD such as Angelman/Prader-Willi or DiGeorge syndrome. Other loci are found on chromosome 1, 2 or 16. Due to short time of studies of cryptic rearrangements, phenotypic variability and number of patients we can expect more researches in the future. These researches are expected not to overlook the impact of the aberrations on formation of autism spectrum disorders.
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Molecular Genetic Analysis in Patients Suspected of Cryptic Rearrangements.
Šolc, Roman ; Hirschfeldová, Kateřina (advisor) ; Vícha, Aleš (referee)
Such chromosomal rearrangements, which cannot be detected by using of cytogenetic banding of metaphase chromosomes, i.e. chromosomes smaller than 3 - 5 Mb, and therefore modern molecular genetic methods are used to detect them, are called "cryptic rearrangements". Their important role in human pathology is more and more significant. By using of the multiplex ligation-probe dependent amplification method (MLPA) we examined a group of 50 probands with idiopathic mental retardation. A cryptic rearrangement was found at 8 probands (16 %), at 6 of them it was demonstrably causal. Then we examined a group of 40 probands suspected of gene SHOX pathology. A cryptic rearrangement was found at 17 probands (42.5 %) and at 8 of them it was demonstrably causal. Presence of small deletion founded isolated at 7 probands was verified in a population set, but without a positive result. An analysis of mutations was made too.
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Analysis of copy number variant (CNV) in genomes of patiens with mental retardation
Hančárová, Miroslava ; Sedláček, Zdeněk (advisor) ; Gaillyová, Renata (referee) ; Michalová, Kyra (referee)
Mental retardation (MR) is a very heterogeneous common neurodevelopmental disorder with a population prevalence of 2.5-3 %. The importance of genetic factors in the development of MR is high but in a significant number of cases the etiology remains unexplained. Recent studies using array methods pointed to frequent occurrence of copy number variants (CNVs) in patients with MR. Pathogenic CNVs were identified in 10-15 % patients with idiopathic MR and normal karyotype. The aim of our work was the analysis of genome-wide gains and losses of genetic material in a group of Czech patients with MR and a thorough bioinformatic analysis of the genetic changes identified aiming at the assessment of their clinical significance. We performed whole genome analysis using the HumanCytoSNP-12 BeadChips (Illumina) in 183 patients with idiopathic MR, normal karyotype and no FMR1 gene expansion. Data analysis was carried out using two independent programmes, GenomeStudio and QuantiSNP. The findings were subjected to two rounds of thorough bioinformatic analysis. Based on this analysis we classified the CNVs into 4 categories: pathogenic CNVs, probably pathogenic CNVs, CNVs with uncertain clinical significance and benign CNVs. With the exception of the benign variants, all CNVs were confirmed using an independent laboratory...
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The significance of the parental origin of the affected chromosome in the development of microdeletion syndromes
Rašpličková, Tereza ; Šolc, Roman (advisor) ; Novotná, Drahuše (referee)
Microdeletion syndromes are complex diseases caused by loss of genetic information resulting from cryptic deletions which are smaller than 5 Mb. They are cause a large number of phenotypic features. Most common are developmental and mental retardations, various physical defects and abnormalities or behavior problems. It has been shown, that in some cases plays a role parental origin of affected chromosome in microdeletion syndrome. In Angelman, Prader-Willi and Beckwith-Wiedemann syndromes is unequal disability of chromosomes caused by genomic imprinting. The reasons for dominance disability of one parental chromosome in Cri du chat syndrome, monosomy 1p36 and Phelan-McDermid syndrome are different and the effect of genomic imprinting has not been confirmed. Key words: microdeletion, microdeletion syndromes, methylation, genomic imprinting
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Cryptic Rearrangements of Human Chromosomes Associated with Schizophrenia
Jurišová, Lívia ; Šolc, Roman (advisor) ; Brynychová, Iva (referee)
Schizophrenia is a severe mental disorder with high heritability and complex genetics which interacts with environmental factors and leads to a wide range of symptoms. The emergence of modern cytogenetic and molecular genetic techniques has allowed uncovering one of the po- ssible causes - cryptic chromosomal rearrangements. The size of rearrangements, also known as microdeletions and microduplications, is under 3-5 Mb. Aberrations may affect multiple genes and their gene dosage. The research of cryptic rearrangements in association with schizophrenia began in 2008 with the identification of three pathogenic aberrations. Over time studies have identified more cryptic rearrangements and new studies supporting or not supporting their role in the disorder have been published. Research of the candidate genes and their possible interac- tions has also been conducted. It is hypothesized that schizophrenia is caused by pathologically changed brain connectivity, in which the changed gene dosage by cryptic rearrangements may play a role. The research is in its beginnings, and we can expect the identification of new rear- rangements. Further research may lead to a better understanding of the origin and symptoms of schizophrenia, and play a role in prenatal diagnostics and treatment. Key words: cryptic...
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Detection of submicroscopics aberrations using arrayCGH
HORÁKOVÁ, Pavla
This thesis addresses array CGH method (Comparative Genomic Hybridization on microarrays) and its use inprenatal and postnatal genetic diagnosis. The method used was to determine the chromosomal areas in which the number of copies of DNA sequences had changed. Localizations of the aberrations sites are not known in advance; the issue is that of all genomic screening. The method is used in suspected cases of microdeletion and microduplication syndromes. It may also be used in cases of patients with pathological phenotypic changes, but other methods have shown no change in genetic makeup. This thesis focuses on diagnosis in the prenatal period and investigates the causes of pathological symptoms in the postnatal diagnosis. Firstly, this thesis describes procedures in clinical cytogenetics and then it discusses submicroscopic changes. Secondly, the thesis looks into the array CGH method, explains its procedure and use, and evaluates and interpretates its results. Finally, the work statistically evaluates the array CGH data procured in the OLG department in Thomayrova hospital from 8/ 8 to 3/19. The array CGH method may be used to supplement routinely administered cytogenetic tests. It enables specialists to obtain more detailed information about the genetic material of an individual and examine the frequency of microdeletion and microduplication syndromes. The diagnosis and prognosis of patients may be determined based on the results.
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Cryptic Rearrangements of Human Chromosomes Associated with Autism Spectrum Disorders
Křivánková, Anna ; Šolc, Roman (advisor) ; Růžičková, Šárka (referee)
Autism spectrum disorders (ASD) are heterogeneous group of neurodevelopmental disabilities characterized by antisociality and atypical behavioral patterns. Its etiology is very complex, autism is usually formed by combining many factors. One of the causes may be genetic (gene mutation). It is known about 450 candidate genes for ASD so far. Minority of these genes occur in loci which are affected by cryptic rearrangements. These rearrangements significantly contribute to manifestation of this disorder. Patologies they cause, lead to syndromes with high penetrance for ASD such as Angelman/Prader-Willi or DiGeorge syndrome. Other loci are found on chromosome 1, 2 or 16. Due to short time of studies of cryptic rearrangements, phenotypic variability and number of patients we can expect more researches in the future. These researches are expected not to overlook the impact of the aberrations on formation of autism spectrum disorders.
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The significance of the parental origin of the affected chromosome in the development of microdeletion syndromes
Rašpličková, Tereza ; Šolc, Roman (advisor) ; Novotná, Drahuše (referee)
Microdeletion syndromes are complex diseases caused by loss of genetic information resulting from cryptic deletions which are smaller than 5 Mb. They are cause a large number of phenotypic features. Most common are developmental and mental retardations, various physical defects and abnormalities or behavior problems. It has been shown, that in some cases plays a role parental origin of affected chromosome in microdeletion syndrome. In Angelman, Prader-Willi and Beckwith-Wiedemann syndromes is unequal disability of chromosomes caused by genomic imprinting. The reasons for dominance disability of one parental chromosome in Cri du chat syndrome, monosomy 1p36 and Phelan-McDermid syndrome are different and the effect of genomic imprinting has not been confirmed. Key words: microdeletion, microdeletion syndromes, methylation, genomic imprinting
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Analysis of clinical features in patients with autism and intellectual disability who were indicated to the investigation using SNP array
Petříková, Nikola ; Vlčková, Markéta (advisor) ; Panczak, Aleš (referee)
This bachelor thesis deals with the analysis of clinical features in patients with autism spectrum disorders who were investigated using DNA microarrays. The introductory section is focused on the definition of autism and its subtypes, on currently known genetic causes of this neurodevelopmental disorder and on the possibilities of the laboratory diagnosis. Autism is likely caused by CNV occurring in different loci of the human genome, which can be efficiently diagnosed using DNA microarrays. This technique enables the detection of many CNV, but in most cases only common population polymorphisms can be identified. Our group consisted of 98 patients who suffered from some subtype of autism spectrum disorder. All patients were investigated using the microarray HumanCytoSNP-12 manufactured by Illumina. A retrospective analysis of clinical features of interest that were found in the medical documentation of the patients was performed. Statistical analysis of the data was performed to find possible associations. Specific pairs of features were compared in more detail. Features with known correlation previously published in the literature or features where a correlation could be expected were selected for this detailed analysis. Some findings were concordant with the published data, but some were not. Finally, it...
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Reciprocal microdeletion and microduplication on human chromosomes
Sluková, Lucie ; Šolc, Roman (advisor) ; Brynychová, Iva (referee)
Nonallelic homologous recombination (NAHR) mediated by LCRs (low-copy repeats) produces chromosomal rearrangements in the human genome. Those rearrangements include microdeletion and microduplication. Those mutations cause a great number of syndromes and thus are studied along with its genesis. Studies are enabled by the development of methods, which are able to detect those cryptic aberrations, e.g. comparative genomic hybridisation (CGH). Nowadays scientists often come across the mirror phenotype of the already described microdeletion (microduplication) syndromes. The presence of the reciprocal microduplication (microdeletion), which afflicted a gene sensitive to gene dosage or other important region of the human genome, is discovered by a genomic analysis. The examples of those affected chromosomal regions (and associated diseases) are areas 1q21.1; 5q35.2-3 (Sotos syndrome); 7q11.23 (Williams-Beuren syndrome); 16p11.2 až 12.2 a 16p13.11; 17q11.2 (Neurofibromatosis type 1); 17p11.2-12 (CMT1A/HNPP) a 22q11.2 (DiGeorge syndrome and VCFS). Key words: microduplication; microdeletion; nonallelic homologous recombination (NAHR); comparative genomic hybridisation (CGH); mirror phenotype; reciprocal rearrangements.
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