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1.
Impaired neurodevelopmental genes in Slovenian autistic children elucidate the comorbidity of autism with other developmental disorders
Danijela Krgović, Mario Gorenjak, Nika Rihar, Iva Opalič, Špela Stangler Herodež, Hojka Gregorič Kumperščak, Peter Dovč, Nadja Kokalj-Vokač, 2022, original scientific article

Abstract: Autism spectrum disorders (ASD) represent a phenotypically heterogeneous group of patients that strongly intertwine with other neurodevelopmental disorders (NDDs), with genetics playing a significant role in their etiology. Whole exome sequencing (WES) has become predominant in molecular diagnostics for ASD by considerably increasing the diagnostic yield. However, the proportion of undiagnosed patients still remains high due to complex clinical presentation, reduced penetrance, and lack of segregation analysis or clinical information. Thus, reverse phenotyping, where we first identified a possible genetic cause and then determine its clinical relevance, has been shown to be a more efficient approach. WES was performed on 147 Slovenian pediatric patients with suspected ASD. Data analysis was focused on identifying ultrarare or “single event” variants in ASD-associated genes and further expanded to NDD-associated genes. Protein function and gene prioritization were performed on detected clinically relevant variants to determine their role in ASD etiology and phenotype. Reverse phenotyping revealed a pathogenic or likely pathogenic variant in ASD-associated genes in 20.4% of patients, with subsequent segregation analysis indicating that 14 were de novo variants and 1 was presumed compound heterozygous. The diagnostic yield was further increased by 2.7% by the analysis of ultrarare or “single event” variants in all NDD-associated genes. Protein function analysis established that genes in which variants of unknown significance (VUS) were detected were predominantly the cause of intellectual disability (ID), and in most cases, features of ASD as well. Using such an approach, variants in rarely described ASD-associated genes, such as SIN3B, NR4A2, and GRIA1, were detected. By expanding the analysis to include functionally similar NDD genes, variants in KCNK9, GNE, and other genes were identified. These would probably have been missed by classic genotype–phenotype analysis. Our study thus demonstrates that in patients with ASD, analysis of ultrarare or “single event” variants obtained using WES with the inclusion of functionally similar genes and reverse phenotyping obtained a higher diagnostic yield despite limited clinical data. The present study also demonstrates that most of the causative genes in our cohort were involved in the syndromic form of ASD and confirms their comorbidity with other developmental disorders.
Keywords: reverse phenotyping, single event variants, NDD-associated genes, GRIA1 gene, NR4A2 gene, SIN3B gene, autism, child
Published in DKUM: 12.12.2024; Views: 0; Downloads: 3
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2.
Detection of aneuploidy using multiplex ligation-dependent probe amplification in fetal tissues from aborted pregnancies
Boris Zagradišnik, Špela Stangler Herodež, Alenka Erjavec Škerget, Andreja Zagorac, Nadja Kokalj-Vokač, 2011, original scientific article

Abstract: Purpose: About 10-15% of all pregnancies terminate as spontaneous miscarriages. In the first trimester, 50% of spontaneous miscarriages are the result of chromosomal aberrations, mostly chromosomal aneuploidies. Cytogenetic analyses are used to confirm aneuploidy in failed pregnancies. Culture failure or poor quality chromosomes are often problems in those cases. In such situations, methods that are independent of tissue culture areused, and we employed multiplex ligation-dependent probe amplification (MLPA). We determined if MLPA is an appropriate and compatible method compared with classical cytogenetic analyses on fetal tissues. Methods: All fetal samples received from spontaneous abortions were cultured, karyotyped (if possible) and genomic DNA extracted. MLPA analyses were undertaken using subtelomeric probe kits. Additionally, comparative genomic hybridization (CGH) was used to confirm aneuploidy detected by MLPA in cases of failed culture growth. Results: MLPA analyses confirmed an unbalanced chromosome abnormality identified by cytogenetic analyses in all cases in which tissue culture was successful, and provided data in cases of failed culture growth. Several common numeric chromosome aberrations were detected, as well as rare trisomies and other unbalanced chromosome rearrangements. Conclusions: MLPA analyses can provide information about the karyotype of a DNA sample if cytogenetic analyses are not possible because of a lack of viable cells or if only a small amount of genomic DNA is available. These data indicate that MLPA may also be a very useful method for early prenatal aneuploidy screening.
Keywords: pomnoževanje od ligacije odvisnih prob, številčne kromosomske preureditve, kariotip
Published in DKUM: 12.04.2024; Views: 230; Downloads: 10
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3.
Detection of vkorc1 polymorphism : comparison of polymerase chain reaction/restriction fragment length polymorphism (pcr + rflp) with allele-specific polymerase chain reaction
Špela Stangler Herodež, Nastja Stankovič, Boris Zagradišnik, Alenka Erjavec Škerget, Nadja Kokalj-Vokač, 2013, original scientific article

Abstract: Purpose: The VKORC1 polymorphism is an important genetic factor affecting warfarin dose requirement. Patients require different warfarin doses in order to achieve the target therapeutic anticoagulation. The aim of our study was to determine the frequency of single nucleotide polymorphisms (SNP) in the VKORC1gene in the general population, using a simple, rapid, and economical method. Methods: For genotyping, the restriction fragment length polymorphism (RFLP) of polymerase chain reaction (PCR) amplified DNA was used and compared to allele specific polymerase chain reaction. We genotyped 441 DNA samples obtained from the healthy general population in North Eastern Slovenia. Genotypes for the tested group were evaluated to determine whether the population followed the Hardy Weinberg equilibrium. The genotypes and allele frequencies were calculated. Results: The results obtained using the allele specific polymerase chain reaction were consistent with those obtained using the PCR + RFLP method. The G allele frequency (0.62) was higher than the A allele frequency (0.38) in the general population from North Eastern Slovenia. Conclusions: The PCR+RFLP method involved additional manipulation of the PCR products at the expense of analysis time, consumption of reagents and equipment. The allele specific polymerase chain reaction was a simple and rapid method for the detection of SNP in theVKORC1 gene, and is available in any laboratory with the minimum of equipment and reagents required.
Keywords: VKORC1, varfarin, PCR, RFLP, alelno specifična verižna reakcija s polimerazo
Published in DKUM: 12.04.2024; Views: 163; Downloads: 4
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4.
Accuracy and speed of molecular response reporting with Xpert BCR-ABL Ultra in vitro diagnostic test in CML patients
Špela Stangler Herodež, Nadja Kokalj-Vokač, Zlatko Roškar, Mojca Dreisinger, 2021, original scientific article

Keywords: chronic myeloid leukemia, BCR-ABL1 fusion gene, GeneXpert, minimal residual disease, molecular response
Published in DKUM: 22.01.2023; Views: 595; Downloads: 63
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5.
Clinicopathologic characteristics of patients with vulvar cancer treated between 1994 and 2017 at the University Medical Centre Maribor
Vida Gavrić-Lovrec, Nejc Kozar, Iztok Takač, Špela Stangler Herodež, 2021, original scientific article

Keywords: vulvar cancer, epidemiology, histology, HPV
Published in DKUM: 22.01.2023; Views: 597; Downloads: 57
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7.
Prisotnost aktivacijskih mutacij v genu PIK3CA in okužbe s HPV virusom v vzorcih raka ustne votline in ustnega dela žrela
Maja Jančar, 2018, master's thesis

Abstract: Izhodišče: Rak ustne votline in ustnega dela žrela je eden izmed najpogostejših rakov na svetu. Tradicionalno je povezan s kajenjem tobaka in pitjem alkohola, vendar se s to vrsto raka vedno bolj povezuje okužba HPV. HPV so zelo razširjeni majhni DNA virusi, ki povzročajo različne novotvorbe. V HPV pozitivnih rakih je najpogosteje mutiran PIK3CA gen, ki je zelo povezan z invazivnostjo raka. Prisotnost aktivacijskih mutacij v genu PIK3CA povzroči okrepitev PIK3K signalne poti v tumorskih tkivih, kar nakazuje, da je PIK3CA vpleten tudi v oblikovanje tumorjev. Metodologija: Opravili smo analizo DNA 108 tumorjev in 88 vzorcev zdravih tkiv ustne votline in ustnega dela žrela. Za določanje prisotnosti HPV, določitev tipa HPV in določanje najpogostejših aktivacijskih mutacij v genu PIK3CA smo uporabili metodo verižne reakcije s polimerazo (PCR). Dobljene produkte PCR smo analizirali s pomočjo elektroforeze v agaroznem gelu. Rezultati: Ugotovili smo, da lahko z metodo verižne reakcije s polimerazo določimo prisotnost HPV DNA v vzorcu kakor tudi mutacije v genu PIK3CA. Sklep: PCR reakcija se je izkazala za uspešno metodo za dokazovanje prisotnosti mutacij v genu PIK3CA kakor tudi za določanje prisotnosti HPV DNA v vzorcu. Za potrditev, da je ta metoda primerna tudi za določitev tipa HPV, pa bi morali celotno analizo opraviti na večjem številu vzorcev.
Keywords: DNA, PCR, ORL tumorji, začetni oligonukleotidi, elektroforeza.
Published in DKUM: 27.09.2018; Views: 1394; Downloads: 126
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8.
MTHFR C677T and A1298C genotypes and haplotypes in Slovenian couples with unexplained infertility problems and in embryonic tissues from spontaneous abortions
Špela Stangler Herodež, Boris Zagradišnik, Alenka Erjavec Škerget, Andreja Zagorac, Iztok Takač, Veljko Vlaisavljević, Lidija Lokar, Nadja Kokalj-Vokač, 2013, original scientific article

Abstract: The objective of this study was to analyze the methylenetetrahydrofolate reductases (MTHFRs) C677T and A1298C genotype distributions in couples with unexplained fertility problems (UFP) and healthy controls, and to analyze the genotype and haplotype distribution in spontaneously aborted embryonic tissues (SAET) using allele specific polymerase chain reaction (PCR) in 200 probands with UFP, 353 samples of SAET and 222 healthy controls. The analysis revealed a significant overall representation of the 677T allele in male probands from couples with UFP (p = 0.036). The combined genotype distribution for both MTHFR polymorphisms was also significantly altered (χ2 21.73, p <0.001) although female probands made no contribution (c2 1.33, p = 0.72). The overall representation of the 677T allele was more pronounced in SAET (0.5 vs. 0.351 in controls, p <0.001) regardless of the karyotype status (aneuploidy vs. normal karyotype). In addition, the frequencies of the CA and CC haplotypes were significantly lower than in the control group (p = 0.021 and p = 0.001, respectively), whereas the frequency of the TC haplotype was significantly higher than in controls (p <0.0001). The presented findings indicate that only male probands contribute to the association of MTHFR mutations with fertility problems in grown adults and demonstrate a high prevalence of mutated MTHFR genotypes in SAET.
Keywords: methylenetetrahydrofolate reductase (MTHFR), genotype, haplotype, infertility, miscarriage
Published in DKUM: 30.03.2017; Views: 1469; Downloads: 316
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9.
Detection of mutations in the CYP21A2 gene : genotype-phenotype correlation in Slovenian couples with conceiving problems
Špela Stangler Herodež, Lusien Fijavž, Boris Zagradišnik, Nadja Kokalj-Vokač, 2015, original scientific article

Abstract: The objective of this study was to compare the CYP 21A2 genetic profiles of couples with unexplained fertility problems (UFP) with genetic profiles of healthy controls (HCs). Furthermore, we analyzed associations between mutations in the CYP21A2 gene and various clinical and laboratory parameters. Allele-specific polymerase chain reaction (PCR) was used in 638 probands with UFP and 200 HCs. Statistic analysis with χ2 was used to study the association of mutations with infertility. The effect of mutations on particular clinical and laboratory parameters was assessed with the analysis of variance (ANOVA) test. With regard to the CYP21A2 gene, 0.6% of probands with UFP and 0.5% of HCs were positive for the c.290-13A/C>G mutation; 0.6% of probands with UFP and 1.5% of HCs were positive for the p.I172N mutation; there were no probands with UFP positive for the p.P30L mutation, whereas 0.5% of HCs were; and 0.2% of probands with UFP and 0.5% of HCs were found to have the p.V281L mutation. We found a significant association between c.290-13A/C>G mutation and the frequency of significant hormone deviations (χ2 = 6.997, p = 0.008). Similar association was also observed between the c.29013A/C>G mutation and the frequency of polycystic ovary syndrome (PCOS) (χ2 = 16.775, p = 0.000). Our findings indicate that no significant difference in the prevalence of CYP 21A2 mutations can be found in probands with UFP when compared with HCs without infertility history. The results also imply the significant association of the c.290-13A/ C>G mutation in the CYP21A2 gene, not only with the frequency of PCOS, but also with the frequency of significant hormone deviations.
Keywords: CYP21A2 gene, genetics, infertility, mutations, unexplained infertility problems (UFP), healthy controls (HCs)
Published in DKUM: 30.03.2017; Views: 1343; Downloads: 179
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10.
PRIMERJAVA NATANČNOSTI DVEH METOD TESTIRANJA ZA PRISOTNOST VIRUSA HEPATITISA C PRI KRVODAJALCIH
Sara Kugler, 2016, undergraduate thesis

Abstract: Namen diplomske naloge je bil primerjati dve metodi testiranja za prisotnost virusa hepatitisa C pri krvodajalcih. Poskušali smo ugotoviti, katera izmed teh dveh metod je natančnejša. V sklopu eksperimentalnega dela, ki smo ga opravljali v Centru za transfuzijsko medicino v Univerzitetnem kliničnem centru Maribor, smo testirali 21 vzorcev krvi krvodajalcev na anti-HCV. Opravili smo primerjavo testov med dvema proizvajalcema reagentov: -ORTHO HCV 3.0 Test System with Enhanced SAVe (Sample Addition Verification), na aparatu BEP 2000, na katerem se izvaja encimsko imunska metoda (ELISA), -Abbott Architect System Anti-HCV, na aparatu Architect i2000, na katerem se izvaja kemiluminiscenčna imunska metoda (CMIA). Pri testiranju z ORTHO reagenti smo dobili en reaktiven vzorec, vsi ostali so bili nereaktivni. Ta vzorec smo zadržali in ponovno testirali v dvojniku, ki je potrdil prvotno ugotovitev, da je ta vzorec reaktiven. Vse vzorce smo nato še enkrat testirali z Abbott reagenti. Ponovno so bili vsi rezultati nereaktivni, razen vzorca, ki se je že izkazal za reaktivnega, je bil tokrat mejno reaktiven. Ta vzorec smo poslali na potrditveni test imunoblot na Zavod Republike Slovenije za transfuzijsko medicino v Ljubljano. Kljub temu, da je bil vzorec krvi po potrjevalnem testiranju negativen, smo vse komponente krvi zaradi reaktivnosti presejalnega testiranja uničili.
Keywords: HCV, testiranje, ELISA, CMIA
Published in DKUM: 04.05.2016; Views: 2162; Downloads: 191
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