| 1. |
- Andersson, Nadine, et al.
(författare)
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Genetic screening of children with suspected inherited bleeding disorders
- 2020
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 26:2, s. 314-324
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Genetic screening using high-throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear.AIM: To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing.METHODS: After informed consent, children (<18 years) with suspected IBD underwent genetic screening with 94 selected genes.RESULTS: A total of 68 heterozygous class 3-5 variants were detected in 30 children, 2.3 variants per patient. Directed specific functional testing was performed after genetic screening in a subset of patients. Adhering to the ACMG guidelines, the results of functional testing together with family history and previous publications classified three variants as likely disease causing (class 4) and two variants as disease causing (class 5), all in children with thrombocytopenia. The overall diagnostic rate was 16.7% (5/30). Children with thrombocytopenia had a significantly higher rate of significant genetic findings, 5/9 (55.6%) vs. 0/21 (0%; P = .0009).CONCLUSION: We conclude that performing genetic screening in children is an effective tool especially for children with inherited thrombocytopenia and has the possibility to diagnose platelet disorders adequately early in life. Children with bleeding diathesis, normal coagulation work-up and without thrombocytopenia are unlikely to be diagnosed by genetic screening. Ethical issues such as incidental findings, variants associated with cancer and the interpretation of the genetic results into clinical practice remain problematic.
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| 2. |
- Hossein Khademi, S. M., et al.
(författare)
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Genomic and phenotypic evolution of achromobacter xylosoxidans during chronic airway infections of patients with cystic fibrosis
- 2021
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Ingår i: mSystems. - 2379-5077. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial pathogens evolve during chronic colonization of the human host by selection for pathoadaptive mutations. One of the emerging and understudied bacterial species causing chronic airway infections in patients with cystic fibrosis (CF) is Achromobacter xylosoxidans. It can establish chronic infections in patients with CF, but the genetic and phenotypic changes associated with adaptation during these infections are not completely understood. In this study, we analyzed the wholegenome sequences of 55 clinical A. xylosoxidans isolates longitudinally collected from the sputum of 6 patients with CF. Four genes encoding regulatory proteins and two intergenic regions showed convergent evolution, likely driven by positive selection for pathoadaptive mutations, across the different clones of A. xylosoxidans. Most of the evolved isolates had lower swimming motility and were resistant to multiple classes of antibiotics, while fewer of the evolved isolates had slower growth or higher biofilm production than the first isolates. Using a genome-wide association study method, we identified several putative genetic determinants of biofilm formation, motility and b-lactam resistance in this pathogen. With respect to antibiotic resistance, we discovered that a combination of mutations in pathoadaptive genes (phoQ and bigR) and two other genes encoding regulatory proteins (spoT and cpxA) were associated with increased resistance to meropenem and ceftazidime. Altogether, our results suggest that genetic changes within regulatory loci facilitate within-host adaptation of A. xylosoxidans and the emergence of adaptive phenotypes, such as antibiotic resistance or biofilm formation. IMPORTANCE A thorough understanding of bacterial pathogen adaptation is essential for the treatment of chronic bacterial infections. One unique challenge in the analysis and interpretation of genomics data is identifying the functional impact of mutations accumulated in the bacterial genome during colonization in the human host. Here, we investigated the genomic and phenotypic evolution of A. xylosoxidans in chronic airway infections of patients with CF and identified several mutations associated with the phenotypic evolution of this pathogen using genome-wide associations. Identification of phenotypes under positive selection and the associated mutations can enlighten the adaptive processes of this emerging pathogen in human infections and pave the way for novel therapeutic interventions.
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| 3. |
- Åkesson, Alexander, et al.
(författare)
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Clinical characterization and identification of rare genetic variants in atypical hemolytic uremic syndrome : a Swedish retrospective observational study
- 2021
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Ingår i: Therapeutic Apheresis and Dialysis. - : Wiley. - 1744-9979 .- 1744-9987. ; 25:6, s. 988-1000
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Complement-mediated atypical hemolytic uremic syndrome (aHUS) is an ultra-rare renal disease primarily caused by genetic alterations in complement proteins. The genetic work-up required for confirmation of diagnosis is complicated and not always logistically accessible. The aim of the present study was to apply a diagnostic scheme compliant with the ACMG guidelines to investigate the prevalence of complement-mediated aHUS among subjects formerly included in a retrospective cohort of clinically suspected aHUS. Clinical outcomes and genetic correlations to complement analyses were assessed.METHODS: Subjects were investigated with medical record reviewing, inquiries and laboratory analyses composed of whole genome sequencing; ELISA for factor I, factor H and factor H-specific antibodies; nephelometry for complement components 3/4; flow cytometry for CD46 surface expression and immunoblotting for the presence of factor H-related protein 1.RESULTS: In total, 45% (n=60/134) of the subjects were deceased at the time of study. Twenty of the eligible subjects consented to study participation. Based on genetic sequencing and clinical characteristics, six were categorized as definite/highly suspected complement-mediated aHUS, ten as non-complement-mediated aHUS and four as having an HUS-like phenotype. In the complement-mediated aHUS group, two subjects had not received an aHUS diagnosis during the routine clinical management. Disease-contributing/likely disease-contributing genetic variants were identified in five subjects, including a novel missense variant in the complement factor H gene (c.3450A>G,p.I1150M).CONCLUSION: The study illustrates the risk for misdiagnosis in the management of patients with complement-mediated aHUS and the importance of a comprehensive assessment of both phenotype and genotype to reach a diagnosis. This article is protected by copyright. All rights reserved.
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