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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.
Preurejanje genov TMPRSS2 in ERG ter njuna prognostična vloga pri slovenskih bolnikih s karcinomom prostate
Zoran Krstanoski, 2017, doctoral dissertation

Abstract: Namen: Rak na prostati (CaP) je najpogostejša rakasta bolezen pri moških in eden glavnih razlogov zbolevnosti in umrljivosti. V zadnjih letih je vse več raziskav o novih tumorskih označevalcih za zgodnjo diagnozo prostatičnega karcinoma. Z dokazanimi napovednimi vrednostmi novih markerjev bi bolje razumeli naravni potek bolezni, omogočili zgodnejše in zanesljivejše odkrivanje karcinoma ter pripomogli k natančnejši napovedi progresa in metastaziranja bolezni pri posamičnem bolniku. Bolniki in metode: Opravili smo retrospektivno raziskavo na vzorcih prostate 202 bolnikov, pri katerih smo zaradi dokazanega karcinoma prostate naredili laparoskopsko radikalno prostatektomijo na urološkem oddelku Splošne bolniš nice Slovenj Gradec. Bolniki so bili operirani v obdobju od januarja 2010 do julija 2011. Morfološke značilnosti in klasične napovedne dejavnike karcinomov smo zbrali iz histopatoloških izvidov in jih potrdili tudi z revizijo preparatov. Za raziskavo smo konstruirali tkivne mreže. Tako pripravljene preparate smo obdelali po metodi fluorescentne hibridizacije in situ. Rezultati: V tumorskem tkivu bolnikov smo odkrili tri glavne oblike preurejanja genov: fuzijo TMPRSS2:ERG smo našli pri 63 (42 %) bolnikih, cepitev TMPRSS2 pri dvanajstih in cepitev ERG pri osmih bolnikih. Fuzijo TMPRSS2:ERG in cepitev TMPRSS2 hkrati smo ugotovili le pri enem bolniku. Pri treh bolnikih smo odkrili istočasno fuzijo TMPRSS2:ERG in cepitev ERG. Ko smo primerjali skupino 63 bolnikov z gensko fuzijo TMPRSS2:ERG in Gleasonov stadij pred operacijo, smo uporabili Freeman-Haltonovo varianto Fisherjevega natančnega testa, pri tem pa med spremenljivkama nismo našli statistične povezave (p = 0,19). Če smo analizirali odnos med gensko fuzijo in stadijem pT v celi kohorti bolnikov, povezave nismo mogli ugotoviti. Ko pa smo razdelili bolnike v dve skupini, eno s stadijem pT2 in drugo s pT3, smo odkrili statistično značilno povezavo med stadijem pT3 in osnovno gensko fuzijo. Med 62 bolniki s stadijem pT3 smo našli gensko fuzijo pri 34 (55 %) bolnikih. Z uporabo Fisherjevega natančnega testa smo odkrili statistično zanesljivost s p = 0,01. Po uporabi Bonferronieve korekcije pa je bila vrednost p še vedno zanesljiva z vrednostjo 0,05. V naslednjem koraku smo preverili še povezavo med gensko fuzijo in stadijem pN. Bolnike z opravljeno elektivno disekcijo bezgavk smo razdelili v dve skupini, in sicer pN0 in pN1. Za ta del odvisnosti smo uporabili Freeman-Haltonovo raširitev Fisherjevega natančnega testa. Med obema spremenljivkama nismo našli statistične povezave (p = 0,66). Za analizo bolnikov z ugotovljenim stadijem N smo izbrali skupino s tumorskim stadijem pT3. Pokazalo se je, da je korelacija z gensko fuzijo statistično značilna (p = 0,02). Ko pa smo uporabili še Bonferronievo korekcijo, vrednost p ni dosegla 0,05. V nadaljnjih statističnih obdelavah smo skupino bolnikov s stadijem pT3 razdelili na dvoje ‒ v skupino z razširjeno limfadenektomijo in skupino brez tega posega. Pri bolnikih, kjer posega nismo opravili, smo gensko fuzijo odkrili v 25 (64 %) primerih. Povezava med gensko fuzijo in to značilnostjo je dosegla statistično vrednost p = 0,039. Zaključek: Na podlagi naših rezultatov pričakujemo, da bi pri bolnikih s fuzijo TMPRSS2:ERG, odkriti že na biopsiji prostate, dokazali stadij T3 po radikalni prostatektomiji v več kot polovici primerov (64 %). Podatek je pomemben predvsem za bolnike s predoperativno nizkimi PSA in GS, kar sicer kaže na rak z nizkim ali zmernim tveganjem, vendar bi tako resno podcenili razširjenost bolezni. Ker bi pri teh bolnikih torej pričakovali lokalno napredovano bolezen oziroma stadij-pT3, bi z radikalnejšim posegom dosegli nižji odstotek pozitivnih robov (ki v zadnjih smernicah še vedno dosegajo 33,5‒66 %). Pri bolnikih s klinič nim stadijem pT3 pričakujemo limfogene metastaze v 7,9‒49 odstotkih.
Keywords: rak prostate, prostatektomija, FISH, genske preureditve, klinič no-patološke korelacije, napovedni dejavniki
Published in DKUM: 17.10.2017; Views: 1822; Downloads: 94
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6.
Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1
Hojka Gregorič Kumperščak, Danijela Krgović, Nadja Kokalj-Vokač, 2016, original scientific article

Abstract: Chromosomal abnormalities involving 2q32q33 deletions are very rare and present with a specific phenotype. This case report describes a 37-year-old female patient with 2q32q33 microdeletion syndrome presenting with the characteristic features, but with the addition of secondary cognitive decline. Molecular karyotyping was performed on the patient and her parents. It revealed an 8.6 megabase deletion with the proximal breakpoint in the chromosome band 2q32.2 and the distal breakpoint in 2q33.1. The deletion encompassed 22 known genes, including the GLS, MYO1B, TMEFF2, PGAP1 and SATB2 genes. The observed deletion was confirmed using a paralogue ratio test. This case report provides further evidence that the SATB2 gene, together with GLS, MYO1B, TMEFF2 and possibly PGAP1, is a crucial gene in 2q32q33 microdeletion syndrome. The SATB2 gene seems to be crucial for the behavioural problems noted in our case, but deletion of the GLS, MYO1B and TMEFF2 genes presumably contributed to the more complex behavioural characteristics observed. Our patient is also, to our knowledge, the only patient with 2q32q33 microdeletion syndrome with secondary cognitive decline.
Keywords: 2q32q33 microdeletion syndrome, behavioural problems, secondary cognitive decline, developmental delay, SATB2 gene
Published in DKUM: 13.07.2017; Views: 1330; Downloads: 377
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7.
Submicroscopic interstitial deletion of chromosome 11q22.3 in a girl with mild mental retardation and facial dysmorphism: Case report
Danijela Krgović, Nataša Marčun-Varda, Andreja Zagorac, Nadja Kokalj-Vokač, 2011, original scientific article

Abstract: Background: Except for terminal deletions that lead to Jacobsen syndrome, interstitial deletions involving the long arm of chromosome 11 are not frequently reported. A clinically distinct phenotype is usually observed in these cases, and no clear genotype-phenotype correlation is proposed. Results: Here we present a case study of a 5-year-old girl with de novo submicroscopic deletion of chromosome 11q22.3 with mild mental retardation and facial dysmorphism. A standard cytogenetic analysis did not reveal any structural aberrations. A contrary array-CGH analysis indicated a small deletion of 11q22.3. Discussion: To our knowledge, this is the smallest 11q22.3 deletion reported in literature, containing nine RefSeq genes. Although none of the deleted genes are obvious candidates for the features observed in our patient, genes CUL5 and SLN could play a key role in the features described.
Keywords: 11q22.3 deletion, mild mental retardation, facial dysmorphism
Published in DKUM: 29.06.2017; Views: 1653; Downloads: 372
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8.
An evaluation of SOX2 and hTERC gene amplifications as screening markers in oral and oropharyngeal squamous cell carcinomas
Nadja Kokalj-Vokač, Bogdan Čizmarevič, Andreja Zagorac, Boris Zagradišnik, Boštjan Lanišnik, original scientific article

Abstract: Background: Oral and oropharyngeal squamous cell carcinomas (OSCC) are among the most common cancers. The poor survival rate among oral cancer patients can be attributed to several factors, one of them being lack of early detection. A key approach to this problem would be to detect potentially malignant lesion at their early stage. Using the FISH technique, oral brush cytology slides can be an easy and rapid screening approach for malignant cell detection. The present study was designed to detect hTERC and SOX2 amplifications in OSSC exfoliative tumor cells and evaluate whether those two gene amplifications might serve as a supportive biomarker in early detection and diagnosis of oral and oropharyngeal SCC. Results: Brush biopsies were collected from exophytic and exulcerated oral and oropharyngeal lesions of the oral cavity of 71 patients and 22 healthy controls. FISH techniques using a TERC-specific DNA probe and a SOX2 DNA specific probe both combined with a centromere 3-specific control probe was performed on the cytology slides. A 100 squamous epithelial cell nuclei of the smears per slide were analysed. As abnormal FISH pattern were considered amplified and polyploid patterns. From 71 brush biopsies of oropharynx and other locations in oral cavity analysed by FISH 49 were considered to be abnormal (69%). The over representation of polyploidy and/or TERC/SOX2 amplification in tumour samples was statistically significant when compared to controls (p = 0.01). Conclusion: SOX2 and TERC gene amplifications are common in all squamous cell carcinomas and their detection in early stages could be crucial for early detection and more accurate prognosis. Our study strongly suggests that early detection by FISH on cytobrushed samples could be a possible non-invasive screening method even before a tissue biopsy is performed.
Keywords: SOX and hTERC gene amplifications, brush biopsy, Oral, oropharyngeal squamous cell carcinoma
Published in DKUM: 29.06.2017; Views: 1403; Downloads: 400
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9.
TMPRSS2:ERG gene aberrations may provide insight into pT stage in prostate cancer
Zoran Krstanoski, Nadja Kokalj-Vokač, Andreja Zagorac, Boris Pospihalj, Miha Munda, Sašo Džeroski, Rastko Golouh, 2016, original scientific article

Abstract: Background: TMPRSS2:ERG gene aberration may be a novel marker that improves risk stratification of prostate cancer before definitive cancer therapy, but studies have been inconclusive. Methods: The study cohort consisted of 202 operable prostate cancer Slovenian patients who underwent laparoscopic radical prostatectomy. We retrospectively constructed tissue microarrays of their prostatic specimens for fluorescence in situ hybridization, with appropriate signals obtained in 148 patients for subsequent statistical analyses. Results: The following genetic aberrations were found: TMPRSS2:ERG fusion, TMPRSS2 split (a non-ERG translocation) and ERG split (an ERG translocation without involvement of TMPRSS2). TMPRSS2:ERG gene fusion happened in 63 patients (42 %), TMPRSS2 split in 12 patients and ERG split in 8 patients. Association was tested between TMPRSS2:ERG gene fusion and several clinicopathological variables, i.e., pT stage, extended lymph node dissection status, and Gleason score, correcting for multiple comparisons. Only the association with pT stage was significant at p = 0.05: Of 62 patients with pT3 stage, 34 (55 %) had TMPRSS2:ERG gene fusion. In pT3 stage patients, stronger (but not significant) association between eLND status and TMPRSS2:ERG gene fusion was detected. We detected TMPRSS2:ERG gene fusion in 64 % of the pT3 stage patients where we did not perform an extended lymph node dissection. Conclusions: Our results indicate that it is possible to predict pT3 stage at final histology from TMPRSS2:ERG gene fusion at initial core needle biopsy. FISH determination of TMPRSS2:ERG gene fusion may be particularly useful for patients scheduled to undergo a radical prostatectomy in order to improve oncological and functional results.
Keywords: FISH, predicting pT stage, radical prostatectomy, prostate cancer, TMPRSS2:ERG fusion
Published in DKUM: 29.06.2017; Views: 1953; Downloads: 413
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10.
A coalescence of two syndromes in a girl with terminal deletion and inverted duplication of chromosome 5
Danijela Krgović, Ana Blatnik, Ante Burmas, Andreja Zagorac, Nadja Kokalj-Vokač, 2014, original scientific article

Abstract: Background: Rearrangements involving chromosome 5p often result in two syndromes, Cri-du-chat (CdC) and Trisomy 5p, caused by a deletion and duplication, respectively. The 5p15.2 has been defined as a critical region for CdC syndrome; however, genotype-phenotype studies allowed isolation of particular characteristics such as speech delay, cat-like cry and mental retardation, caused by distinct deletions of 5p. A varied clinical outcome was also observed in patients with Trisomy 5p. Duplications of 5p10-5p13.1 manifest themselves in a more severe phenotype, while trisomy of regions distal to 5p13 mainly causes mild and indistinct features. Combinations of a terminal deletion and inverted duplication of 5p are infrequent in literature. Consequences of these chromosomal rearrangements differ, depending on size of deletion and duplication in particular cases, although authors mainly describe the deletion as the cause of the observed clinical picture. Case presentation: Here we present a 5-month-old Slovenian girl, with de novo terminal deletion and inverted duplication of chromosome 5p. Our patient presents features of both CdC and Trisomy 5. The most prominent features observed in our patient are a cat-like cry and severe malformations of the right ear. Conclusion: The cat-like cry, characteristic of CdC syndrome, is noted in our patient despite the fact that the deletion is not fully consistent with previously defined cat-like cry critical region in this syndrome. Features like dolichocephaly, macrocephaly and ear malformations, associated with duplication of the critical region of Trisomy 5p, are also present, although this region has not been rearranged in our case. Therefore, the true meaning of the described chromosomal rearrangements is discussed.
Keywords: deletion with inverted duplication of 5p, trisomy 5, cri-du-chat syndrome, cat-like cry, ear agenesis
Published in DKUM: 28.06.2017; Views: 1566; Downloads: 401
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