| 1. |
- Kapferer-Seebacher, Ines, et al.
(författare)
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Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement
- 2016
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Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 99:5, s. 1005-1014
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Tidskriftsartikel (refereegranskat)abstract
- Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.
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| 2. |
- Lindstrand, Anna, et al.
(författare)
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From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
- 2019
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Ingår i: Genome Medicine. - : BMC. - 1756-994X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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| 3. |
- Tham, Emma, et al.
(författare)
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A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9.
- 2015
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813.
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Tidskriftsartikel (refereegranskat)abstract
- A rare lethal autosomal recessive syndrome with skeletal dysplasia, polycystic kidneys and multiple malformations was first described by Gillessen-Kaesbach et al and subsequently by Nishimura et al. The skeletal features uniformly comprise a round pelvis, mesomelic shortening of the upper limbs and defective ossification of the cervical spine. We studied two unrelated families including three affected fetuses with Gillessen-Kaesbach-Nishimura syndrome using whole-exome and Sanger sequencing, comparative genome hybridization and homozygosity mapping. All affected patients were shown to have a novel homozygous splice variant NM_024740.2: c.1173+2T>A in the ALG9 gene, encoding alpha-1,2-mannosyltransferase, involved in the formation of the lipid-linked oligosaccharide precursor of N-glycosylation. RNA analysis demonstrated skipping of exon 10, leading to shorter RNA. Mass spectrometric analysis showed an increase in monoglycosylated transferrin as compared with control tissues, confirming that this is a congenital disorder of glycosylation (CDG). Only three liveborn children with ALG9-CDG have been previously reported, all with missense variants. All three suffered from intellectual disability, muscular hypotonia, microcephaly and renal cysts, but none had skeletal dysplasia. Our study shows that some pathogenic variants in ALG9 can present as a lethal skeletal dysplasia with visceral malformations as the most severe phenotype. The skeletal features overlap with that previously reported for ALG3- and ALG12-CDG, suggesting that this subset of glycosylation disorders constitutes a new diagnostic group of skeletal dysplasias.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.91.
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| 4. |
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| 5. |
- Eisfeldt, Jesper, et al.
(författare)
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Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:16
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Tidskriftsartikel (refereegranskat)abstract
- Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient's cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient's cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.
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| 6. |
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| 7. |
- Kvarnung, Malin, et al.
(författare)
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Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186
- 2019
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The etiology of hereditary ataxia syndromes is heterogeneous, and the mechanisms underlying these disorders are often unknown. Here, we utilized exome sequencing in two siblings with progressive ataxia and muscular weakness and identified a novel homozygous splice mutation (c.3020-1G > A) in neurofascin (NFASC). In RNA extracted from fibroblasts, we showed that the mutation resulted in inframe skipping of exon 26, with a deprived expression of the full-length transcript that corresponds to NFASC isoform NF186. To further investigate the disease mechanisms, we reprogrammed fibroblasts from one affected sibling to induced pluripotent stem cells, directed them to neuroepithelial stem cells and finally differentiated to neurons. In early neurogenesis, differentiating cells with selective depletion of the NF186 isoform showed significantly reduced neurite outgrowth as well as fewer emerging neurites. Furthermore, whole-cell patch-clamp recordings of patient-derived neuronal cells revealed a lower threshold for openings, indicating altered Na+ channel kinetics, suggesting a lower threshold for openings as compared to neuronal cells without the NFASC mutation. Taken together, our results suggest that loss of the full-length NFASC isoform NF186 causes perturbed neurogenesis and impaired neuronal biophysical properties resulting in a novel early-onset autosomal recessive ataxia syndrome.
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| 8. |
- Lindstrand, Anna, et al.
(författare)
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Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability
- 2022
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Ingår i: Genetics in Medicine. - : ELSEVIER SCIENCE INC. - 1098-3600 .- 1530-0366. ; 24:11, s. 2296-2307
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 9. |
- Magnusson, Måns, et al.
(författare)
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Loqusdb : added value of an observations database of local genomic variation
- 2020
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Ingår i: BMC Bioinformatics. - : Springer Nature. - 1471-2105. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Exome and genome sequencing is becoming the method of choice for rare disease diagnostics. One of the key challenges remaining is distinguishing the disease causing variants from the benign background variation. After analysis and annotation of the sequencing data there are typically thousands of candidate variants requiring further investigation. One of the most effective and least biased ways to reduce this number is to assess the rarity of a variant in any population. Currently, there are a number of reliable sources of information for major population frequencies when considering single nucleotide variants (SNVs) and small insertion and deletions (INDELs), with gnomAD as the most prominent public resource available. However, local variation or frequencies in sub-populations may be underrepresented in these public resources. In contrast, for structural variation (SV), the background frequency in the general population is more or less unknown mostly due to challenges in calling SVs in a consistent way. Keeping track of local variation is one way to overcome these problems and significantly reduce the number of potential disease causing variants retained for manual inspection, both for SNVs and SVs. Results Here, we present loqusdb, a tool to solve the challenge of keeping track of any type of variant observations from genome sequencing data. Loqusdb was designed to handle a large flow of samples and unlike other solutions, samples can be added continuously to the database without rebuilding it, facilitating improvements and additions. We assessed the added value of a local observations database using 98 samples annotated with information from a background of 888 unrelated individuals. Conclusions We show both how powerful SV analysis can be when filtering for population frequencies and how the number of apparently rare SNVs/INDELs can be reduced by adding local population information even after annotating the data with other large frequency databases, such as gnomAD. In conclusion, we show that a local frequency database is an attractive, and a necessary addition to the publicly available databases that facilitate the analysis of exome and genome data in a clinical setting.
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| 10. |
- Pramling, Ingrid, et al.
(författare)
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27 forskare i upprop mot skärmfri förskola
- 2024
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Ingår i: Förskolan. - Stockholm : Sveriges Lärare.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- VI LÄRARE DEBATT: Regeringens uppdrag till Skolverket – att göra utbildningen i förskolan skärmfri – riskerar att ge negativa och allvarliga konsekvenser, särskilt för barn som är i störst behov av att möta en digitaliserad värld med stöd av utbildade förskollärare och barnskötare. Det skriver 27 barn- och förskoleforskare i ett gemensamt upprop.
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| 11. |
- Pramling Samuelsson, Ingrid, et al.
(författare)
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27 forskare i upprop mot skärmfri förskola
- 2024
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Ingår i: Förskolan. - Stockholm : Sveriges Lärare.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- VI LÄRARE DEBATT: Regeringens uppdrag till Skolverket – att göra utbildningen i förskolan skärmfri – riskerar att ge negativa och allvarliga konsekvenser, särskilt för barn som är i störst behov av att möta en digitaliserad värld med stöd av utbildade förskollärare och barnskötare. Det skriver 27 barn- och förskoleforskare i ett gemensamt upprop.
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| 12. |
- Rasi, Chiara, et al.
(författare)
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PatientMatcher : A customizable Python-based open-source tool for matching undiagnosed rare disease patients via the Matchmaker Exchange network
- 2022
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Ingår i: Human Mutation. - : Wiley. - 1059-7794 .- 1098-1004. ; 43:6, s. 708-716
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Tidskriftsartikel (refereegranskat)abstract
- The amount of data available from genomic medicine has revolutionized the approach to identify the determinants underlying many rare diseases. The task of confirming a genotype–phenotype causality for a patient affected with a rare genetic disease is often challenging. In this context, the establishment of the Matchmaker Exchange (MME) network has assumed a pivotal role in bridging heterogeneous patient information stored on different medical and research servers. MME has made it possible to solve rare disease cases by “matching” the genotypic and phenotypic characteristics of a patient of interest with patient data available at other clinical facilities participating in the network. Here, we present PatientMatcher (https://github.com/Clinical-Genomics/patientMatcher), an open-source Python and MongoDB-based software solution developed by Clinical Genomics facility at the Science for Life Laboratory in Stockholm. PatientMatcher is designed as a standalone MME server, but can easily communicate via REST API with external applications managing genetic analyses and patient data. The MME node is being implemented in clinical routine in collaboration with the Genomic Medicine Center Karolinska at the Karolinska University Hospital. PatientMatcher is written to implement the MME API and provides several customizable settings, including a custom-fit similarity score algorithm and adjustable matching results notifications.
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| 13. |
- Rodriguez-Palmero, Agusti, et al.
(författare)
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DLG4-related synaptopathy : a new rare brain disorder
- 2021
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 23:5, s. 888-899
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Tidskriftsartikel (refereegranskat)abstract
- PurposePostsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.MethodsThe clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.ResultsThe clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.ConclusionThe present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
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| 14. |
- Runheim, Hannes, et al.
(författare)
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The cost-effectiveness of whole genome sequencing in neurodevelopmental disorders
- 2023
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Ingår i: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Whole genome sequencing (WGS) has the potential to be a comprehensive genetic test, especially relevant for individuals with neurodevelopmental disorders, syndromes and congenital malformations. However, the cost consequences of using whole genome sequencing as a first-line genetic test for these individuals are not well understood. The study objective was to compare the healthcare costs and diagnostic yield when WGS is performed as the first-line test instead of chromosomal microarray analysis (CMA). Two cohorts were analyzed retrospectively using register data, cohort CMA (418 patients referred for CMA at the department of Clinical Genetics, Karolinska University Hospital, during 2015) and cohort WGS (89 patients included in a WGS-first prospective study in 2017). The analysis compared healthcare consumption over a 2-year period after referral for genetic testing, the diagnostic yield over a 2- and 3-year period after referral was also compiled. The mean healthcare cost per patient in cohort WGS was $2,339 lower compared to cohort CMA ($ - 2339, 95% CI - 12,238-7561; P = 0.64) including higher costs for genetic investigations ($1065, 95% CI 834-1295; P < 0.001) and lower costs for outpatient care ($ - 2330, 95% CI - 3992 to (- 669); P = 0.006). The diagnostic yield was 23% higher for cohort WGS (cohort CMA 20.1%, cohort WGS 24.7%) (0.046, 95% CI - 0.053-0.145; P = 0.36). WGS as a first-line diagnostic test for individuals with neurodevelopmental disorders is associated with statistically non-significant lower costs and higher diagnostic yield compared with CMA. This indicates that prioritizing WGS over CMA in health care decision making will yield positive expected outcomes as well as showing a need for further research.
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| 15. |
- Schuy, Jakob, et al.
(författare)
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Partial Monosomy 21 Mirrors Gene Expression of Trisomy 21 in a Patient-Derived Neuroepithelial Stem Cell Model
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Induced pluripotent stem cells (iPSCs) from patients are an attractive disease model to study tissues with poor accessibility such as the brain. Using this approach, we and others have shown that trisomy 21 results in genome-wide transcriptional dysregulations. The effects of loss of genes on chromosome 21 is much less characterized. Here, we use patient-derived neural cells from an individual with neurodevelopmental delay and a ring chromosome 21 with two deletions spanning 3.8 Mb at the terminal end of 21q22.3, containing 60 protein-coding genes. To investigate the molecular perturbations of the partial monosomy on neural cells, we established patient-derived iPSCs from fibroblasts retaining the ring chromosome 21, and we then induced iPSCs into neuroepithelial stem cells. RNA-Seq analysis of NESCs with the ring chromosome revealed downregulation of 18 genes within the deleted region together with global transcriptomic dysregulations when compared to euploid NESCs. Since the deletions on chromosome 21 represent a genetic “contrary” to trisomy of the corresponding region, we further compared the dysregulated transcriptomic profile in with that of two NESC lines with trisomy 21. The analysis revealed opposed expression changes for 23 genes on chromosome 21 as well as 149 non-chromosome 21 genes. Taken together, our results bring insights into the effects on the global and chromosome 21 specific gene expression from a partial monosomy of chromosome 21qter during early neuronal differentiation.
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| 16. |
- Tesi, Bianca, et al.
(författare)
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Precision medicine in rare diseases : What is next?
- 2023
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 294:4, s. 397-412
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Forskningsöversikt (refereegranskat)abstract
- Molecular diagnostics is a cornerstone of modern precision medicine, broadly understood as tailoring an individual's treatment, follow-up, and care based on molecular data. In rare diseases (RDs), molecular diagnoses reveal valuable information about the cause of symptoms, disease progression, familial risk, and in certain cases, unlock access to targeted therapies. Due to decreasing DNA sequencing costs, genome sequencing (GS) is emerging as the primary method for precision diagnostics in RDs. Several ongoing European initiatives for precision medicine have chosen GS as their method of choice. Recent research supports the role for GS as first-line genetic investigation in individuals with suspected RD, due to its improved diagnostic yield compared to other methods. Moreover, GS can detect a broad range of genetic aberrations including those in noncoding regions, producing comprehensive data that can be periodically reanalyzed for years to come when further evidence emerges. Indeed, targeted drug development and repurposing of medicines can be accelerated as more individuals with RDs receive a molecular diagnosis. Multidisciplinary teams in which clinical specialists collaborate with geneticists, genomics education of professionals and the public, and dialogue with patient advocacy groups are essential elements for the integration of precision medicine into clinical practice worldwide. It is also paramount that large research projects share genetic data and leverage novel technologies to fully diagnose individuals with RDs. In conclusion, GS increases diagnostic yields and is a crucial step toward precision medicine for RDs. Its clinical implementation will enable better patient management, unlock targeted therapies, and guide the development of innovative treatments.
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| 17. |
- Åkerfeldt, Anna, et al.
(författare)
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"Fridolin backar in i framtiden om digitala läromedel"
- 2021
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Ingår i: Dagens Nyheter. - 1101-2447. ; :2021-12-16
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Ingress: 23 forskare inom it- och utbildningsområdet: Regeringens utredare borde inte lyfta fram läsning på skärm som något negativt.Forskning visar att både tryckta och digitala läromedel behövs i skolan.
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| 18. |
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| 19. |
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| 20. |
- Ali, Abdulemir, et al.
(författare)
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Similar patient-reported outcomes and performance after total knee arthroplasty with or without patellar resurfacing : A randomized study of 74 patients with 6 years of follow-up
- 2016
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Ingår i: Acta Orthopaedica. - : Informa UK Limited. - 1745-3674 .- 1745-3682. ; 87:3, s. 274-279
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose — Knee pain after total knee arthroplasty (TKA) is not uncommon. Patellar retention in TKA is one cause of postoperative knee pain, and may lead to secondary addition of a patellar component. Patellar resurfacing in TKA is controversial. Its use ranges from 2% to 90% worldwide. In this randomized study, we compared the outcome after patellar resurfacing and after no resurfacing. Patients and methods — We performed a prospective, randomized study of 74 patients with primary osteoarthritis who underwent a Triathlon CR TKA. The patients were randomized to either patellar resurfacing or no resurfacing. They filled out the VAS pain score and KOOS questionnaires preoperatively, and VAS pain, KOOS, and patient satisfaction 3, 12, and 72 months postoperatively. Physical performance tests were performed preoperatively and 3 months postoperatively. Results — We found similar scores for VAS pain, patient satisfaction, and KOOS 5 subscales at 3, 12, and 72 months postoperatively in the 2 groups. Physical performance tests 3 months postoperatively were also similar in the 2 groups. No secondary resurfacing was performed in the group with no resurfacing during the first 72 months Interpretation — Patellar resurfacing in primary Triathlon CR TKA is of no advantage regarding pain, physical performance, KOOS 5 subscales, or patient satisfaction compared to no resurfacing. None of the patients were reoperated with secondary addition of a patellar component within 6 years. According to these results, routine patellar resurfacing in primary Triathlon TKA appears to be unnecessary.
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| 21. |
- Anh, Nhi, et al.
(författare)
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High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing
- 2018
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome-wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements. Samples were selected based on cytogenetic and FISH results at leukemia diagnosis to include common rearrangements of prognostic relevance. Using MP-WGS and in-house bioinformatic analysis all sought rearrangements were successfully detected. In addition, unexpected complexity or additional, previously undetected rearrangements was unraveled in three samples. Finally, the MP-WGS analysis pinpointed the location of chromosome junctions at high resolution and we were able to identify the exact exons involved in the resulting fusion genes in all samples and the specific junction at the nucleotide level in half of the samples. The results show that our approach combines the screening character from karyotype analysis with the specificity and resolution of cytogenetic and molecular methods. As a result of the straightforward analysis and high-resolution detection of clinically relevant rearrangements, we conclude that MP-WGS is a feasible method for routine leukemia diagnostics of structural chromosomal rearrangements.
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| 22. |
- Aranda-Guillén, Maribel, et al.
(författare)
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A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies.
- 2023
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Ingår i: Journal of internal medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 294:1, s. 96-109
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients.We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI.The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p<2e-16), and 1.2 SD higher in the young patients compared with the old (p=3e-4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies.The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.
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| 23. |
- Bieder, Andrea, et al.
(författare)
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Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia : a case report
- 2020
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Ingår i: BMC Medical Genetics. - : Springer. - 1471-2350. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies. Case presentation Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified. Conclusions We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.
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| 24. |
- Chrapkowska, Cecilia, et al.
(författare)
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Validation of the new Swedish vaccination register – Accuracy and completeness of register data
- 2020
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 38:25, s. 4104-4110
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aims of this study are to validate infant vaccination data in the Swedish Vaccination Register (SVR) to the Swedish administrative coverage reports, and to assess differences in register-based vaccination coverage estimates between providers using different data reporting methods. Methods: The study population included all infants born in Sweden with a Swedish Personal Identity Number during 2014 and 2015 (n = 230,220). Data on all National Immunisation Programme vaccinations administered before 24 months of age were collected from the SVR and from administrative coverage reports. Information regarding data registration methods in the SVR were collected from national and regional authorities. Coverage from health care providers using single registration methods, where vaccination data were transferred automatically from the electronic health care record to the SVR, was compared to that from providers using double registration methods where data had to be added into the SVR in a separate process. Results: For 98,4% of the study population at least one vaccination was recorded in the SVR. The coverage of 3-dose DTP-containing (87,1%) and 1 dose MMR (91,1%) in the register did not reach administrative data coverage (97,4% for 3-dose DTP-containing and 97,0% for MMR). Single registration procedures yielded significantly higher coverage than double registration procedures (92,24% vs 87,10%, p < 0,0001). A regional switch from double to single registration increased coverage from 80,0 to 95,2%. Conclusions: The SVR is a valuable data source for vaccination coverage monitoring. For research purposes, the SVR provides valuable data, since every health care provider is obliged to register all vaccine doses given within the national immunisation program. The SVR shows a high completeness validated by comparison to a very well-functioning administrative data system. Single-registration procedures give more complete data and should be supported by health systems while creating health care registers.
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| 25. |
-
Didaktik i omvandlingens tid : Text, representation, design
- 2017. - 1
-
Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- I Didaktik i omvandlingens tid ger författarna en bred syn på didaktik och på hur miljöer och resurser utformas för att understödja lärande. Boken tar avstamp i en tid då kommunikation blir alltmer utvecklad genom ny teknologi. Hur lärare använder teknologin får då avgörande betydelse för undervisningen. Författarna sätter fokus på design för lärande och multimodalitet och betonar särskilt de kreativa och mångfasetterade aspekterna av lärande, undervisning och bedömning.
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| 26. |
- Edsjö, Anders, et al.
(författare)
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Building a precision medicine infrastructure at a national level : The Swedish experience
- 2023
-
Ingår i: Cambridge Prisms: Precision Medicine. - : Cambridge University Press. - 2752-6143. ; 1
-
Forskningsöversikt (refereegranskat)abstract
- Precision medicine has the potential to transform healthcare by moving from one-size-fits-all to personalised treatment and care. This transition has been greatly facilitated through new high-throughput sequencing technologies that can provide the unique molecular profile of each individual patient, along with the rapid development of targeted therapies directed to the Achilles heels of each disease. To implement precision medicine approaches in healthcare, many countries have adopted national strategies and initiated genomic/precision medicine initiatives to provide equal access to all citizens. In other countries, such as Sweden, this has proven more difficult due to regionally organised healthcare. Using a bottom-up approach, key stakeholders from academia, healthcare, industry and patient organisations joined forces and formed Genomic Medicine Sweden (GMS), a national infrastructure for the implementation of precision medicine across the country. To achieve this, Genomic Medicine Centres have been established to provide regionally distributed genomic services, and a national informatics infrastructure has been built to allow secure data handling and sharing. GMS has a broad scope focusing on rare diseases, cancer, pharmacogenomics, infectious diseases and complex diseases, while also providing expertise in informatics, ethical and legal issues, health economy, industry collaboration and education. In this review, we summarise our experience in building a national infrastructure for precision medicine. We also provide key examples how precision medicine already has been successfully implemented within our focus areas. Finally, we bring up challenges and opportunities associated with precision medicine implementation, the importance of international collaboration, as well as the future perspective in the field of precision medicine.
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| 27. |
- Eisfeldt, Jesper, et al.
(författare)
-
Discovery of Novel Sequences in 1,000 Swedish Genomes
- 2020
-
Ingår i: Molecular biology and evolution. - : OXFORD UNIV PRESS. - 0737-4038 .- 1537-1719. ; 37:1, s. 18-30
-
Tidskriftsartikel (refereegranskat)abstract
- Novel sequences (NSs), not present in the human reference genome, are abundant and remain largely unexplored. Here, we utilize de novo assembly to study NS in 1,000 Swedish individuals first sequenced as part of the SweGen project revealing a total of 46 Mb in 61,044 distinct contigs of sequences not present in GRCh38. The contigs were aligned to recently published catalogs of Icelandic and Pan-African NSs, as well as the chimpanzee genome, revealing a great diversity of shared sequences. Analyzing the positioning of NS across the chimpanzee genome, we find that 2,807 NS align confidently within 143 chimpanzee orthologs of human genes. Aligning the whole genome sequencing data to the chimpanzee genome, we discover ancestral NS common throughout the Swedish population. The NSs were searched for repeats and repeat elements: revealing a majority of repetitive sequence (56%), and enrichment of simple repeats (28%) and satellites (15%). Lastly, we align the unmappable reads of a subset of the thousand genomes data to our collection of NS, as well as the previously published Pan-African NS: revealing that both the Swedish and Pan-African NS are widespread, and that the Swedish NSs are largely a subset of the Pan-African NS. Overall, these results highlight the importance of creating a more diverse reference genome and illustrate that significant amounts of the NS may be of ancestral origin.
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| 28. |
- Eisfeldt, J, et al.
(författare)
-
Hybrid sequencing resolves two germline ultra-complex chromosomal rearrangements consisting of 137 breakpoint junctions in a single carrier
- 2021
-
Ingår i: Human genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 140:5, s. 775-790
-
Tidskriftsartikel (refereegranskat)abstract
- Chromoanagenesis is a genomic event responsible for the formation of complex structural chromosomal rearrangements (CCRs). Germline chromoanagenesis is rare and the majority of reported cases are associated with an affected phenotype. Here, we report a healthy female carrying two de novo CCRs involving chromosomes 4, 19, 21 and X and chromosomes 7 and 11, respectively, with a total of 137 breakpoint junctions (BPJs). We characterized the CCRs using a hybrid-sequencing approach, combining short-read sequencing, nanopore sequencing, and optical mapping. The results were validated using multiple cytogenetic methods, including fluorescence in situ hybridization, spectral karyotyping, and Sanger sequencing. We identified 137 BPJs, which to our knowledge is the highest number of reported breakpoint junctions in germline chromoanagenesis. We also performed a statistical assessment of the positioning of the breakpoints, revealing a significant enrichment of BPJ-affecting genes (96 intragenic BPJs, 26 genes,p < 0.0001), indicating that the CCRs formed during active transcription of these genes. In addition, we find that the DNA fragments are unevenly and non-randomly distributed across the derivative chromosomes indicating a multistep process of scattering and re-joining of DNA fragments. In summary, we report a new maximum number of BPJs (137) in germline chromoanagenesis. We also show that a hybrid sequencing approach is necessary for the correct characterization of complex CCRs. Through in-depth statistical assessment, it was found that the CCRs most likely was formed through an event resembling chromoplexy—a catastrophic event caused by erroneous transcription factor binding.
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| 29. |
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| 30. |
- Eriksson Lindstrand, Anna, et al.
(författare)
-
Playful learning about light and shadow : a learning study project in early childhood education
- 2016
-
Ingår i: Creative Education. - 2151-4755 .- 2151-4771. ; 7:2, s. 333-348
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose of the project was to explore how a learning study (LS) based on variation theory could support the development of playful physics learning in early childhood education. The study explored what patterns of variation used during a three-cycle LS challenged and developed children’s ways of discerning why a shadow occurred. The empirical material comprised a screening (n = 7), three video-documented interventions, and 78 individual pre- and post-test interviews (n = 39) at 4 - 5 years old. Three somewhat different patterns of variation were implemented within a playful frame in the three groups. The results indicate low and non/significant improvements in cycle A, somewhat higher and significant improvements in cycle B, and substantially higher and significant improvements in cycle C. The study indicates a promising ability to combine a playful approach with the variation theory perspective to stimulate children’s understanding of a quite advanced scientific phenomenon. The careful process of identifying potential critical aspects, the awareness of the relationship between the whole and its parts, and the concretization of simultaneity are discussed as key aspects of these findings.
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| 31. |
- Eriksson Lindstrand, Anna, et al.
(författare)
-
Playful learning about light and shadow : a learning study project in early childhood education
- 2016
-
Ingår i: Creative Education. - : Scientific Research Publishing, Inc.. - 2151-4755 .- 2151-4771. ; 7:2, s. 333-348
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose of the project was to explore how a learning study (LS) based on variation theory could support the development of playful physics learning in early childhood education. The study explored what patterns of variation used during a three-cycle LS challenged and developed children’s ways of discerning why a shadow occurred. The empirical material comprised a screening (n = 7), three video-documented interventions, and 78 individual pre- and post-test interviews (n = 39) at 4 - 5 years old. Three somewhat different patterns of variation were implemented within a playful frame in the three groups. The results indicate low and non/significant improvements in cycle A, somewhat higher and significant improvements in cycle B, and substantially higher and significant improvements in cycle C. The study indicates a promising ability to combine a playful approach with the variation theory perspective to stimulate children’s understanding of a quite advanced scientific phenomenon. The careful process of identifying potential critical aspects, the awareness of the relationship between the whole and its parts, and the concretization of simultaneity are discussed as key aspects of these findings.
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| 32. |
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| 33. |
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| 34. |
- Frisk, Sofia, et al.
(författare)
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Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth
- 2019
-
Ingår i: Clinical Genetics. - : WILEY. - 0009-9163 .- 1399-0004. ; 96:2, s. 118-125
-
Tidskriftsartikel (refereegranskat)abstract
- PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles.
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| 35. |
- Hofmeister, Wolfgang, et al.
(författare)
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CTNND2-a candidate gene for reading problems and mild intellectual disability.
- 2015
-
Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 52:2, s. 111-22
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders.METHODS AND RESULTS: Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon.CONCLUSIONS: Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.
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| 36. |
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| 37. |
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| 38. |
- Korberg, Izabella Baranowska, et al.
(författare)
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WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish
- 2015
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:18, s. 5069-5078
-
Tidskriftsartikel (refereegranskat)abstract
- Bladder exstrophy, a severe congenital urological malformation when a child is born with an open urinary bladder, is the most common form of bladder exstrophy-epispadias complex (BEEC) with an incidence of 1: 30,000 children of Caucasian descent. Recent studies suggest that WNT genes may contribute to the etiology of bladder exstrophy. Here, we evaluated WNT-pathway genes in 20 bladder exstrophy patients using massively parallel sequencing. In total 13 variants were identified in WNT3, WNT6, WNT7A, WNT8B, WNT10A, WNT11, WNT16, FZD5, LRP1 and LRP10 genes and predicted as potentially disease causing, of which seven variants were novel. One variant, identified in a patient with a de novo nonsynonymous substitution in WNT3 (p.Cys91Arg), was further evaluated in zebrafish. Knock down of wnt3 in zebrafish showed cloaca malformations, including disorganization of the cloaca epithelium and expansion of the cloaca lumen. Our study suggests that the function of the WNT3 p.Cys91Arg variant was altered, since RNA overexpression of mutant Wnt3 RNA does not result in embryonic lethality as seen with wild-type WNT3 mRNA. Finally, we also mutation screened the WNT3 gene further in 410 DNA samples from BEEC cases and identified one additional mutation c.638G> A (p.Gly213Asp), which was paternally inherited. In aggregate our data support the involvement of WNT-pathway genes in BEEC and suggest that WNT3 in itself is a rare cause of BEEC.
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| 39. |
- Kvarnung, Malin, et al.
(författare)
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Inherited mosaicism for the supernumerary marker chromosome in cat eye syndrome : Inter- and intra-individual variation and correlation to the phenotype
- 2012
-
Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 158A:5, s. 1111-1117
-
Tidskriftsartikel (refereegranskat)abstract
- We have studied a family with repeated transmission of mosaicism for a supernumerary marker chromosome (SMC), giving rise to varying symptoms of the cat eye syndrome (CES) in the offspring. The frequency of the SMC was investigated using FISH with probes from the CES critical region on lymphocytes as well as buccal cells. The same probes were used to study the frequency of the SMC in spermatozoa from the father. The SMC was characterized in detail using array-CGH and was found to correspond to a symmetrical cat eye SMC type I, with two extra copies of the most proximal part of 22q11, not extending into the classical 22q11.2 deletion region. Mosaicism for the SMC was detected in 4 out of 7 family members, the father and all his three children. The degree of mosaicism varied greatly between individuals as well as between tissues, with twice as many cells with the SMC in epithelial cells compared to blood. The highest frequency (almost 50%) was found in spermatozoa from the father. There was a direct correlation between the degree of mosaicism and the symptoms, varying from no obvious symptoms to classical CES. The study confirms the occurrence of direct transmission of SMC-mosaicism in CES. The results indicate that examination of parental epithelial cells should be preferred compared to blood cells in order to exclude a recurrence risk in parents of a child with CES. Interphase FISH analysis of spermatozoa is the most sensitive method to exclude paternal germ line mosaicsm. (c) 2012 Wiley Periodicals, Inc.
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| 40. |
- Laurell, Tobias, et al.
(författare)
-
Identification of three novel FGF16 mutations in X-linked recessive fusion of the fourth and fifth metacarpals and possible correlation with heart disease.
- 2014
-
Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley. - 2324-9269. ; 2:5, s. 402-411
-
Tidskriftsartikel (refereegranskat)abstract
- Nonsense mutations in FGF16 have recently been linked to X-linked recessive hand malformations with fusion between the fourth and the fifth metacarpals and hypoplasia of the fifth digit (MF4; MIM#309630). The purpose of this study was to perform careful clinical phenotyping and to define molecular mechanisms behind X-linked recessive MF4 in three unrelated families. We performed whole-exome sequencing, and identified three novel mutations in FGF16. The functional impact of FGF16 loss was further studied using morpholino-based suppression of fgf16 in zebrafish. In addition, clinical investigations revealed reduced penetrance and variable expressivity of the MF4 phenotype. Cardiac disorders, including myocardial infarction and atrial fibrillation followed the X-linked FGF16 mutated trait in one large family. Our findings establish that a mutation in exon 1, 2 or 3 of FGF16 results in X-linked recessive MF4 and expand the phenotypic spectrum of FGF16 mutations to include a possible correlation with heart disease.
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| 41. |
- Levine, Hagai, et al.
(författare)
-
Male reproductive health statement (XIIIth international symposium on Spermatology, may 9th-12th 2018, Stockholm, Sweden
- 2018
-
Ingår i: Basic and Clinical Andrology. - : Springer Science and Business Media LLC. - 2051-4190. ; 28:1
-
Tidskriftsartikel (refereegranskat)abstract
- On the occasion of the XIIIth International Symposium on Spermatology held from 9 to 13 May 2018 in Stockholm (Sweden), participants (guest speakers and audience) collectively felt the need to make a public statement on the general issue of male reproductive health. Our intention is to raise awareness of what we believe is a neglected area of research despite alarming situations around the world. The disclosure strategy desired by the co-authors is to bring it to the attention of the greatest number partly by considering co-publication in the various periodicals dealing with Reproductive Biology and Andrology. BaCA's editorial office accepted this mission and found it natural that our periodical, the official journal of the French Andrology Society (SALF), should carry this message.
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| 42. |
- Lindstrand, Anna
(författare)
-
Characterization of chromosome abnormalities
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inborn chromosome abnormalities are a frequent cause of mental retardation and birth defects. Apart from aberrations that are visible in the microscope, a number of submicroscopic alterations have recently been discovered, and all of these chromosome changes are in fact the result of DNA alterations at the molecular level. In order to fully understand the mechanisms and consequences behind chromosome changes it is therefore important to characterize the breakpoints in detail. Moreover, the breakpoints are not evenly distributed in the genome. The recurrent genomic disorders illustrate how genomic architectural features make specific chromosomal regions susceptible to non-allelic homologous recombination. Recent technological advances have enabled high resolution, genome-wide analysis and the structure of several non-recurrent aberrations has been clarified. In addition, an unexpectedly high number of complex rearrangements have been detected. We have used molecular cytogenetic methods to characterize the breakpoints of chromosome abnormalities. FISH and array-CGH were used to map the breakpoints and for the detection of genomic imbalances. By customizing arrays it was possible to increase the resolution in a targeted genomic region of interest and determine the structure of the breakpoints with high accuracy, as well as to detect very small imbalances. We were able to identify and narrow down minimal chromosomal regions of overlap in patients with partial deletions and duplications of the same chromosomal region. In two of the these, we actually narrowed down the deletion/duplication region to include only one candidate gene. Hence, deletion of ITSN1 on chromosome 21 seems to be involved in severe mental retardation and duplication of YWHAE, on chromosome 17, was associated with autism. Two extremely complex, intrachromosomal rearrangements of chromosome 1 and 21 were found to include 14 and 16 breakpoints, respectively. These are the most complex chromosome rearrangements involving only a single chromosome that have been reported. We also used targeted custom oligonucleotide arrays to fine map the breakpoints from both balanced and unbalanced rearrangements, and demonstrated that it is possible to characterize unbalanced breakpoints within 17 to 20 000 base pairs, depending on the structure of the genome. The deletion and duplication breakpoints were further refined, and did not seem to be associated with low copy repeats, thus diverse molecular mechanisms are probably responsible for these rearrangements. Contrary to previous reports, we were unable to detect any clinically significant imbalances within the breakpoint regions in patients with apparently balanced reciprocal translocations. The results of this thesis emphasizes the importance of different molecular cytogenetic techniques in the investigation of chromosome aberrations. Our results illustrate that array-CGH is a convenient method to detect and map genomic deletions and duplications with high resolution. However, FISH-analysis remains an important tool to map and characterize both balanced and unbalanced rearrangements and to unravel the complexity of the genomic imbalances detected by array. By combining the two approaches, we have been able to characterize the breakpoints of deletions, duplications, reciprocal translocations and complex rearrangements in detail.
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| 43. |
- Lindstrand, Anna, et al.
(författare)
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Molecular and clinical characterization of patients with overlapping 10p deletions
- 2010
-
Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 152A:5, s. 1233-1243
-
Tidskriftsartikel (refereegranskat)abstract
- Chromosome 10p terminal deletions have been associated with DiGeorge phenotype, and within the same genomic region haploinsufficiency of GATA3 causes the HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia). We have performed detailed molecular analysis of four patients with partial overlapping 10p deletions by using FISH-mapping, array-CGH, and custom-designed high-resolution oligonucleotide array. All four patients had mental retardation and speech impairment and three of them showed variable signs of HDR syndrome. In addition, two patients had autistic behaviors and had similar dysmorphic features giving them a striking physical resemblance. A review of the literature identified 10 previously published cases with similar 10p deletions and reliable molecular or molecular cytogenetic mapping data. The combined information of present and previous cases suggests that partial deletions of 10p14-p15 represent a syndrome with a distinct and more severe phenotype than previously assumed. The main characteristics include severe mental retardation, language impairment, autistic behavior, and characteristic clinical features. A critical region involved in mental retardation and speech impairment is defined within 1.6 Mb in 10p15.3. In addition, deletion of 4.3 Mb within 10p14 is associated with autism and characteristic clinical findings.
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| 44. |
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| 45. |
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| 46. |
- Ljusberg, Anna-Lena, 1957-, et al.
(författare)
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Interviewing children in remedial classes
- 2007
-
Ingår i: International Journal of Rehabilitation Research. - 0342-5282 .- 1473-5660. ; 30:3, s. 203-207
-
Tidskriftsartikel (refereegranskat)abstract
- This study concerns the ethical issues related to interviews with children. In a sub study of the Basic Skills, Social Interaction and Training of the Working Memory (BASTA) project, 10 children between 10 and 12 years of age were interviewed. Interviews involving children have to address many more ethical issues than interviews with adults. Children constitute an overexposed group because they are under age, and because they stand in a dependent relationship with adults. One ethical dilemma for the researcher in interviews with children might be the conflict between professional secrecy and the obligation to report, as stated in the Swedish Social Services Act. According to this Act and to ethical research principles, researchers are bound to maintain professional secrecy.
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| 47. |
- Ljusberg, Anna-Lena, 1957-
(författare)
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Pupils in remedial classes
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this dissertation is to increase understanding of being a pupil in a remedial class. The thesis is based on interviews, questionnaires, and observations and includes parents, teachers, and pupils in ten remedial classes. Fifty-five percent of the studied pupils had no specific diagnosis. The thesis is based on five articles emanating from the interdisciplinary BASTA project (Basic skills, social interaction and training of the working memory). Article I focuses on self-concept, with a rating scale completed by the children. In Article II ethical issues related to the methodology of interviewing children are stressed. Article III focuses on teaching children in remedial classes, and is based on questionnaires completed by teachers and parents. Article IV is based on interviews with pupils. Article V is based on interviews with teachers and on classroom observations, and highlights the classroom climate. The theoretical approach used is a sociocultural perspective. From this perspective, learning is seen as becoming involved in different discourses, where interaction is seen as part of learning and development. The results of the thesis show that the pupils become bearers of the school’s perspective and blame the referral to remedial class on shortcomings in themselves. In transferring to the remedial class the pupils can lose their friends. Factors that reinforce this construction are the structured teaching and organisation of the classroom. These may hinder the pupils both in terms of friendship and of learning of subject knowledge. The main result is, however, that what the pupils in remedial classes primarily learn is to be pupils in remedial classes.
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| 48. |
- Lundin, Johanna, et al.
(författare)
-
Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene
- 2019
-
Ingår i: Molecular Genetics and Genomic Medicine. - : Wiley. - 2324-9269. ; 7:6
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The bladder exstrophy-epispadias complex (BEEC) is a congenital malformation of the bladder and urethra. The underlying causes of this malformation are still largely unknown; however, aside from environment, genetics is thought to play an essential role. The recurrent 22q11.2 microduplication is the most persistently detected genetic aberration found in BEEC cases. Methods: We performed array comparative genomic hybridization (array-CGH) analysis of 76 Swedish BEEC patients. Statistical analysis was performed on current dataset pooled with previously published data on the 22q11.2 microduplication in BEEC patients. We performed massive parallel sequencing (MPS) of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication followed by functional studies. Results: We identified three additional cases with the 22q11.2 microduplication. Pooling data from this study with previously published reports showed a statistically significant enrichment of the 22q11.2 microduplication in BEEC patients (2.61% in cases vs. 0.08% in controls; OR = 32.6; p = 8.7 × 10−4). MPS of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication identified a novel variant in LZTR1 (p.Ser698Phe) in one patient. Functional evaluation of the LZTR1 p.Ser698Phe variant in live NIH 3T3 cells showed that the concentration and cytoplasmic mobility differ between the Lztr1wt and Lztr1mut, indicating a potential functional effect of the LZTR1mut. Conclusion: Our study further emphasizes the involvement of the 22q11.2 region in BEEC development and highlights LZTR1 as a candidate gene underlying the urogenital malformation.
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| 49. |
- Nazaryan-Petersen, Lusine, et al.
(författare)
-
Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization
- 2018
-
Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 14:11
-
Tidskriftsartikel (refereegranskat)abstract
- Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements.
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| 50. |
- Pena-Perez, Lucia, et al.
(författare)
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Linked-read whole-genome sequencing resolves common and private structural variants in multiple myeloma
- 2022
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:17, s. 5009-5023
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is an incurable and aggressive plasma cell malignancy characterized by a complex karyotype with multiple structural variants (SVs) and copy-number variations (CNVs). Linked-read whole-genome sequencing (lrWGS) allows for refined detection and reconstruction of SVs by providing long-range genetic information from standard short-read sequencing. This makes lrWGS an attractive solution for capturing the full genomic complexity of MM. Here we show that high-quality lrWGS data can be generated from low numbers of cells subjected to fluorescence-activated cell sorting (FACS) without DNA purification. Using this protocol, we analyzed MM cells after FACS from 37 patients with MM using lrWGS. We found high concordance between lrWGS and fluorescence in situ hybridization (FISH) for the detection of recurrent translocations and CNVs. Outside of the regions investigated by FISH, we identified > 150 additional SVs and CNVs across the cohort. Analysis of the lrWGS data allowed for resolution of the structure of diverse SVs affecting the MYC and t(11;14) loci, causing the duplication of genes and gene regulatory elements. In addition, we identified private SVs causing the dysregulation of genes recurrently involved in translocations with the IGH locus and show that these can alter the molecular classification of MM. Overall, we conclude that lrWGS allows for the detection of aberrations critical for MM prognostics and provides a feasible route for providing comprehensive genetics. Implementing lrWGS could provide more accurate clinical prognostics, facilitate genomic medicine initiatives, and greatly improve the stratification of patients included in clinical trials.
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