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Mutation Screening in Familial Cardiovascular Diseases
Čapek, Pavel ; Brdička, Radim (advisor) ; Gregor, Pavel (referee) ; Baxová, Alice (referee)
Introduction: Hypertrophic cardiomyopathy is a congenital cardiac disease with autosomal dominant pattern of inheritance and incomplete penetrance. With the knowledge of the responsible genes, the ability to detect the underlying genetic change and with the study of functional analysis of defected protein, we might be able to determine whether specific genotypes lead to different phenotypes. Aims of Study: To comprehensively analyze the mechanism of genesis of hypertrophic cardiomyopathy in Czech patients afflicted with this disorder from molecular genetic point of view (MYH7, TNNT2 gene) to functional analysis of the 3D molecular model of defected β-myosin heavy chain protein in silico. Beside these aims of the study, the reduction of production of inflammatory aggregates in the cardiovascular system was studied in patients with type 2 diabetes mellitus. The reason of this study was to look into possibilities of therapeutical effect on selected cardiovascular risks in patients with hypertrophic cardiomyopathy simultaneously suffering from type 2 diabetes mellitus. Both of these groups of patients have substantially increased risk of cardiovascular diseases due to development of premature atherosclerosis. Material and Methods: A total of 170 probands were enrolled in this study of MYH7 gene. DNA...
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Genotype-phenotype correlation in selected rare disorders using molecular analysis of genome and gene variants
Vlčková, Markéta ; Sedláček, Zdeněk (advisor) ; Gaillyová, Renata (referee) ; Baxová, Alice (referee)
The work was focused on detailed analysis of patients with rare genomic and gene variants. We studied the impact of these variants on the phenotype of the patients. As the majority of our patients, both syndromic and non-syndromic, were reffered to the detailed analysis due to intellectual disability and/or autism spectrum disorder, the work was focused on these two clinical diagnoses. At the beginning we analyzed patients with aberrations detected using cytogenetic analysis, and the extent, gene content and mechanism of origin of the aberrations were refined using molecular genetic methods, most often high-resolution array CGH. Later we analyzed patients with rare or unique submicroscopic aberrations detected using aCGH or SNP array. Using these methodes we analysed in the project patients with deletions of Xp22.1-p22.3, 6q11-q13, 6q14-q16, Xq25, 1q21.1, Xp21.2-p21.3, 2p14-p15, 17q21.31, 9q21.3 a 2p15- p16.1, and a patient with an Xp21.2-p21.3 duplication. In the last years we proceeded to the analysis of syndromic cases using next generation sequencing. This led to the identification of point mutations in the HCFC1, KAT6B, SOS2 and KMT2D genes, which were further studied. The work contributed to the knowledge about the impact of the genome and gene variants identified on the phenotype of the...
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Genetics of Craniosynostosis.
Valterová, Simona ; Křepelová, Anna (advisor) ; Baxová, Alice (referee)
Craniosynostoses are premature fusions of one or more cranial sutures. They affect all cranial sutures and are the main symptom of many genetic syndromes. Syndromes connected with craniosynostosis are serious disorders associated with skeleton abnormalities, limb malformations or mental disability. These syndroms are caused by different mutations in FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, RECQL4, and RAB23 genes. The aim of this review was to summarize contemporary knowledge of phenotype and genetic basis of these diseases.
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Inherited Disorders of Bilirubin Metabolism
Šlachtová, Lenka ; Martásek, Pavel (advisor) ; Baxová, Alice (referee)
Inherited disorders of bilirubin metabolism - hereditary hyperbilirubinemias - are metabolic disorders manifested in early childhood. Unconjugated hyperbilirubinemias result from the defect of the enzyme uridine diphosphoglucuronosyltransferase (UGT1A1). UGT1A1 mediates the conjugation of bilirubin with glucuronid acid in hepatocytes and its elimination to water soluble compound. In the next step of bilirubin degradation the transport of conjugated bilirubin from hepatocyte into the bile occure. It is caused by the ATP dependent transporters ABCC2, ATP1B1 and OATP1B3. Mutations in the genes coding the bilirubin transporters results in conjugated hyperbilirubinemia Dubin-Johnson or Rotor syndrome. This study is focused on unconjugated hyperbilirubinemia in adolescents including the non-typical manifestations and the defects of ABCC2 transporter and their phenotype in humans.
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Molecular syndromology: molecular genetic causes of rare diseases illustrated with Kabuki and Kabuki-like syndromes
Paděrová, Jana ; Macek, Milan (advisor) ; Baxová, Alice (referee) ; Fajkusová, Lenka (referee)
Kabuki syndrome (KS) is a dominantly inherited rare disease caused mainly by de novo pathogenic variants (henceforward mutations) in the KMT2D (formerly MLL2) and KDM6A genes. It is rare multisystemic syndrome characterized by intellectual disability (ID) and typical facial dysmorphism. KS is clinically heterogeneous, which complicates its clinical diagnosis. The first aim of this thesis was to introduce mutation testing of the two known KS causative genes in KS by Sanger DNA sequencing and by MLPA (Multiple Ligation Probe Amplification) at the Department of Biology and Medical Genetics of 2nd Medical Faculty of Charles University and University Hospital Motol, Prague followed by identification of underlying genetic mutations in KMT2D/KDM6A genes in 43 patients with phenotype typical for KS, who were indicated for this molecular genetic analysis by several collaborating genetic departments in the Czech Republic. We aimed to confirm or disprove of patient's clinical diagnosis, establish spectra of KMT2D/KDM6A mutations in the Czech population, render phenotype-genotype correlations and evaluate the phenotypic "MLL2-score" (published by Makrithanasis et al., 2013) utility as prediction tool for selection of cases for KMT2D sequencing. Mutations in the KMT2D gene were detected by Sanger DNA sequencing...
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Anorexia nervosa - selected genetic determinants and endophenotypes
Kaminská, Deborah ; Papežová, Hana (advisor) ; Baxová, Alice (referee) ; Pacák, Karel (referee)
Anorexia Nervosa (AN) and Bulimia Nervosa (BN) are diseases with considerable individual variation. Genetic background plays an important role in disease susceptibility and severity. To evaluate the relationship between certain genetic loci and diseases subtypes we genotyped and analysed evolution of selected clinical parameters. We investigated a group of 75 pacients with AN (1. study), 127 DSM-4 and ICD-10 diagnosed patients with AN and BN (2. study), and contributed to sample of 2907 AN patients in large GWAS study. Results from the 1st study support association of polymorphism -1438G/A in serotonine receptor 5-HT2A with AN and compare the results from other studies with metaanalyses. In next, polymorphism responsible for the serotonine neurotransmission (serotonine transporter 5-HTT, polymorphisms LPR and VNTR) the study shows different association trend of LPR with AN in Czech population compared to other studies. 5-HTT VNTR polymorphism had no observed association. The second study investigated the role of hemeoxygenase 1 (plays a pivotal role in metabolic stress protecting cells) in eating disorders, in interaction with enviromental stress. We investigated the usefulness of an aggregate measure of the risks of AN and BN that is based on genetic susceptibility loci and the added effect of...
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Molecular genetic examinations in clinically defined group of patients with syndromic sight and hearing impairment in rare genetic disorders associated with deafblindness in the CR and SR
Čopíková, Jana ; Kremlíková Pourová, Radka (advisor) ; Astl, Jaromír (referee) ; Baxová, Alice (referee)
Deafblindness is a combined impairment of vision and hearing with an incidence of about 1: 8000 children and 1: 5500 adults. The most common genetic causes are the Stickler (STL) and Usher (USH) syndromes. The main goal of this work is to provide an up-to-date overview of STL and USH in the Czech and Slovak Republic (CR and SR), to determine the correlations between the genotype and phenotype in our population and the associated diagnostic criteria. Using sequencing and MLPA we examined 45 patients from 28 families for suspected STL. We found potentially causal variants of STL genes in 39 patients from 22 families. Fifteen different COL2A1 variants (8 being novel) were found in 28 patients from 18 families and 4 novel COL11A1 variants were found in 11 patients from 4 families. We identified the cause of the disease in 79 % of the families. The USH study involved 30 patients from 27 families. The most frequent cause was USH2A pathogenic variants, i.e. 19 variants in 14 families, 9 being novel. Less common were pathogenic variants in MYO7A (6 variants in 3 families, 5 being novel), USH1C and CDH23 (3 variants, 2 being novel, in 2 families both) genes. In 2 families, compound heterozygosity was found for variants in two different USH genes. The deafblindness etiology was clarified for 24 patients from...
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New Aneuploidy Ultrasound Markers in First Trimester of Pregnancy
Břešťák, Miroslav ; Calda, Pavel (advisor) ; Kacerovský, Marian (referee) ; Baxová, Alice (referee)
Prenatal diagnostics is headed in several directions - towards visualization of fetuses and biochemical, cytogenetic and molecular genetic diagnostics in laboratories. Whereas visualization of fetuses does not a priori represent any direct risk for pregnancy and does not increase the number of potential pregnancy complications, this is not always the case with the laboratory testing. There are known risks connected with invasive methods of prenatal diagnostics. The number of potential unintentional pregnancy complications and losses as well as the technical and economic aspects of invasive prenatal diagnostics lead to attempts of identifying ways of detecting any potentially affected individuals by screening methods, thus minimizing the undesirable impact of invasive diagnostics on the pregnant population. The more precise the selective criteria, the lesser the number of pregnant women exposed to invasive exams. Another way of decreasing the number of unintentional complications in relation to invasive diagnostics is to simplify and improve the fetal samples harvesting methods during pregnancy. The work primarily focused on two areas: Determination of the relation between fraction shortening of the left and right ventricles and a fetal chromosomal complement, and verification of reliability of a new method...
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The impact of IGF1 and selected IGF1 gene polymorphisms on postnatal growth in children SGA/IUGR and extremely preterm newborns.
Kytnarová, Jitka ; Zeman, Jiří (advisor) ; Baxová, Alice (referee) ; Houšťková, Hana (referee)
Long-term outcome of extremely preterm neonates depends on many endogenous and exogenous factors. Long-term follow-up of extremely preterm neonates during childhood and analyses of IGF1 gene polymorphisms may help to better understand the problems connected with delayed postnatal growth and the progression of cardiovascular diseases and diabetes mellitus type 2 in adulthood. The aim was the long-term follow-up of anthropometric parameters in children born at 22−25th and 26−27th week of gestation and to study the association between postnatal growth of extremely preterm children, children small for gestational age (SGA) and children born at term with appropriate birth weight/length (AGA) and IGF1 gene polymorphisms: (CA)10-24 repetitive polymorphism in promoter, microsatellite marker D12S318 and 185 bp in 3'UTR, (CT)n polymorphism (CA)n polymorphism 216 bp in the intron 2. Methods. 242 infants born at 22-27+6 weeks were enrolled. Anthropometric parameters were measured at the ages of 2 and 5 years in 72 children born at 22-25+6 week (group I) and 85 children born at 26-27+6 week (group II). Polymorphisms of IGF1 were analysed in 51 extremely preterm, 208 AGA and 59 SGA children using fragment analyses. The data of postnatal growth data in AGA children were obtained at 18 months, in SGA and extremely...
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