Abstract Background Individuals with familial hypercholesterolemia (FH) who are untreated have up to 100-fold elevated risk for cardiovascular complications compared with those who are unaffected. ...Data for identification of FH with a universal screening for hypercholesterolemia in children are lacking. Objectives This study sought genetic identification of FH from a cohort of children with elevated serum total cholesterol (TC) concentration, detected in a national universal screening for hypercholesterolemia. Methods Slovenian children born between 1989 and 2009 (n = 272) with TC >6 mmol/l (231.7 mg/dl) or >5 mmol/l (193.1 mg/dl) plus a family history positive for premature cardiovascular complications, identified in a national universal screening for hypercholesterolemia at 5 years of age were genotyped for variants in LDLR , PCSK9 , APOB , and APOE. Results Of the referred children, 57.0% carried disease-causing variants for FH: 38.6% in LDLR , 18.4% in APOB , and none in PCSK9 . Nine novel disease-causing variants were identified, 8 in LDLR , and 1 in APOB . Of the remaining participants, 43.6% carried the APOE E4 isoform. Estimated detection rate of FH in the universal screening program from 2009 to 2013 was 53.6% (95% confidence interval CI: 34.5% to 72.8%), peaking in 2013 with an upper estimated detection rate of 96.3%. Variants in LDLR , APOB , or the APOE E4 isoform occurred in 48.6%, 60.0%, and 76.5%, respectively, of patients with a family history negative for cardiovascular complications. Conclusions Most participants who were referred from a national database of universal screening results for hypercholesterolemia had genetically confirmed FH. Data for family history may not suffice for reliable identification of patients through selective and cascade screening.
Type 1 diabetes (T1D) is one of the most common chronic diseases of the endocrine system, associated with several life-threatening comorbidities. While the etiopathogenesis of T1D remains elusive, a ...combination of genetic susceptibility and environmental factors, such as microbial infections, are thought to be involved in the development of the disease. The prime model for studying the genetic component of T1D predisposition encompasses polymorphisms within the
(human leukocyte antigen) region responsible for the specificity of antigen presentation to lymphocytes. Apart from polymorphisms, genomic reorganization caused by repeat elements and endogenous viral elements (EVEs) might be involved in T1D predisposition. Such elements are human endogenous retroviruses (HERVs) and non-long terminal repeat (non-LTR) retrotransposons, including long and short interspersed nuclear elements (LINEs and SINEs). In line with their parasitic origin and selfish behaviour, retrotransposon-imposed gene regulation is a major source of genetic variation and instability in the human genome, and may represent the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. Autoreactive immune cell subtypes with differentially expressed retrotransposons can be identified with single-cell transcriptomics, and personalized assembled genomes can be constructed, which can then serve as a reference for predicting retrotransposon integration/restriction sites. Here we review what is known to date about retrotransposons, we discuss the involvement of viruses and retrotransposons in T1D predisposition, and finally we consider challenges in retrotransposons analysis methods.
In this study, we aimed to identify patients within our B-ALL cohort with altered
. Our objective was to use a comprehensive analysis approach to characterize the types of genetic changes, determine ...their origin (somatic/germline), and analyze the clinical outcomes associated with them. A consecutive cohort of 99 patients with B-ALL treated at the Children's Hospital of the UMC Ljubljana according to the ALL IC-BFM 2009 protocol was included in our study. We used RNA sequencing data for gene expression analysis, fusion gene detection and single nucleotide variant identification, multiplex-ligation dependent probe amplification for copy number variation assessment, and Sanger sequencing for germline variant detection.
was impacted in 33.3% of our patients, with the genetic alterations ranging from CNVs and rearrangements to SNVs. The most common were CNVs, which were found in more than a third of patients, followed by point mutations in 5.2%, and gene rearrangements in 4.1%. We identified eight patients with a
-associated genetic subtype that were previously classified as "B-other", and they showed intermediate outcomes. We showed higher minimal residual disease values at the end of induction and poorer event-free survival in hyperdiploid cases carrying duplications in
compared to other hyperdiploid cases. We also report an interesting case of a patient with
and a pathogenic variant in
who underwent an early relapse with a monocytic switch. In conclusion, this study provides valuable insights into the presence, frequency, and prognostic significance of diverse
alterations in B-ALL patients, highlighting the complexity of genetic factors and their impact on patient outcomes.
Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. It generally occurs in genetically susceptible ...individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. In this review, we highlight the interplay between genetic predisposition and other non-genetic factors, such as viral infections, diet, and gut biome, which all potentially contribute to the aetiology of T1D. We also discuss a possible active role for β-cells in initiating the pathological processes. Another component in T1D predisposition is epigenetic influences, which represent a link between genetic susceptibility and environmental factors and may account for some of the disease heterogeneity. Accordingly, a shift towards personalized therapies may improve the treatment results and, therefore, result in better outcomes for individuals in the long-run. There is also a clear need for a better understanding of the preclinical phases of T1D and finding new predictive biomarkers for earlier diagnosis and therapy, with the final goal of reverting or even preventing the development of the disease.
Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common autoinflammatory disease in children and is often grouped together with hereditary periodic fever ...syndromes, although its cause and hereditary nature remain unexplained. We investigated whether differential DNA methylation was present in DNA from peripheral blood mononuclear cells (PBMC) in patients with PFAPA vs. healthy controls. A whole-epigenome analysis (MeDIP and MBD) was performed using pooled DNA libraries enriched for methylated genomic regions and identified candidate genes, two of which were further evaluated with methylation-specific restriction enzymes coupled with qPCR (MSRE-qPCR). The analysis showed that the
and
gene regions are differentially methylated in patients with PFAPA. MSRE-qPCR proved to be a quick, reliable, and cost-effective method of confirming results from MeDIP and MBD. Our findings indicate that a B-cell adapter protein (
), as the PI3K binding inhibitor of inflammation, and spondin-2 (
), as a pattern recognition molecule and integrin ligand, could play a role in the etiology of PFAPA. Their role and the impact of changed DNA methylation in PFAPA etiology and autoinflammation need further investigation.
Predstavljamo raziskavo o mnenju stanovalcev domov za starejše o izobraževanju na kulturno-umetniškem področju. V raziskavi nas je uvodoma zanimalo, kakšno je mnenje o pomenu izobraževanja na ...kulturno-umetniškem področju, v nadaljevanju pa smo posebno pozornost namenili ugotavljanju obstoja razlik v mnenju o pomembnosti izobraževanja na kulturno-umetniškem področju glede na spol, najvišjo stopnjo pridobljene izobrazbe, izvorno okolje in starost. Raziskovalni vzorec je vključeval 77 udeležencev, ki bivajo v domovih za starejše v Mariboru. Izsledki raziskave kažejo, da se velika večina starejših oseb zaveda pomena izobraževanja na kulturno-umetniškem področju. Ob tem se je izkazalo, da moški in osebe z višjo stopnjo izobrazbe izobraževanju na kulturno-umetniškem področju pripisujejo večji pomen kot ženske in tisti z nižjo stopnjo izobrazbe, medtem ko pri kategorijah izvorno okolje in starost ni bilo zaznati večjih razlik. Pridobljene ugotovitve lahko služijo kot smernice za nadaljnje načrtovanje in raziskovanje izobraževanja na kulturno-umetniškem področju pri starejših osebah, ki bivajo v domovih.
Background Prolonged hyperglycemia causes diabetes-related micro- and macrovascular complications, which combined represent a significant burden for individuals living with diabetes. The growing ...scope of evidence indicates that hyperglycemia affects the development of vascular complications through DNA methylation. Methods A genome-wide differential DNA methylation analysis was performed on pooled peripheral blood DNA samples from individuals with type 1 diabetes (T1D) with direct DNA sequencing. Strict selection criteria were used to ensure two age- and sex-matched groups with no clinical signs of chronic complications according to persistent mean glycated hemoglobin (HbA1c) values over 5 years: HbA1c<7% (N=10) and HbA1c>8% (N=10). Results Between the two groups, 8385 differentially methylated CpG sites, annotated to 1802 genes, were identified. Genes annotated to hypomethylated CpG sites were enriched in 48 signaling pathways. Further analysis of key CpG sites revealed four specific regions, two of which were hypermethylated and two hypomethylated, associated with long non-coding RNA and processed pseudogenes. Conclusions Prolonged hyperglycemia in individuals with T1D, who have no clinical manifestation of diabetes-related complications, is associated with multiple differentially methylated CpG sites in crucial genes and pathways known to be linked to chronic complications in T1D.
Phosphoribosylpyrophosphate synthetase 1 (PRSI) is an enzyme involved in nucleotide metabolism. Pathogenic variants in the PRPS1 are rare and PRS-I deficiency can manifest as three clinical ...syndromes: X-linked non-syndromic sensorineural deafness (DFN2), X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5) and Arts syndrome. We present a Slovenian patient with PRS-I enzyme deficiency due to a novel pathogenic variant – c.424G > A (p.Val142Ile) in the PRPS1 gene, who presented with gross motor impairment, severe sensorineural deafness, balance issues, ataxia, and frequent respiratory infections. In addition, we report the findings of a systemic literature review of all described male cases of Arts syndrome and CMTX5 as well as intermediate phenotypes. As already proposed by other authors, our results confirm PRS-I deficiency should be viewed as a phenotypic continuum rather than three separate syndromes because there are multiple reports of patients with an intermediary clinical presentation.
Our study aimed to identify relevant transcriptomic biomarkers for the Wilms tumor, the most common pediatric kidney cancer, independent of the histological type and stage. Using next-generation ...sequencing, we analyzed the miRNA profiles of 74 kidney samples, which were divided into two independent groups: fresh frozen tissue and formalin-fixed paraffin-embedded tissue samples. Subsequent mRNA expression profiling and pathway analysis were performed to establish the interplay and potential involvement of miRNAs and mRNA in the Wilms tumor. Comparative analysis, irrespective of post-dissection tissue processing, revealed 41 differentially expressed miRNAs, with 27 miRNAs having decreased expression and 14 miRNAs having increased expression in the Wilms tumor tissue compared to healthy kidney tissue. Among global mRNA transcriptomic profile differences, cross-sectional analysis suggested a limited list of genes potentially regulated by differentially expressed miRNAs in the Wilms tumor. This study identified the comprehensive miRNA and mRNA profile of the Wilms tumor using next-generation sequencing and bioinformatics approach, providing better insights into the pathogenesis of the Wilms tumor. The identified Wilms tumor miRNAs have potential as biomarkers for the diagnosis and treatment of the Wilms tumor, regardless of histological subtype and disease stage.
Genomic structural variations, previously considered rare events, are widely recognized as a major source of inter-individual variability and hence, a major hurdle in optimum patient stratification ...and disease management. Herein, we focus on large complex germline structural variations and present challenges towards target treatment via the synergy of state-of-the-art approaches and information technology tools. A complex structural variation detection remains challenging, as there is no gold standard for identifying such genomic variations with long reads, especially when the chromosomal rearrangement in question is a few Mb in length. A clinical case with a large complex chromosomal rearrangement serves as a paradigm. We feel that functional validation and data interpretation are of outmost importance for information growth to be translated into knowledge growth and hence, new working practices are highlighted.
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