| 1. |
- Casslén, Beatrice, et al.
(author)
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Health-related quality of life and functional vision in individuals with retinoblastoma treated with ocular prothesis
- 2023
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In: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology. - 0146-0404 .- 1552-5783. ; 64:8
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Journal article (other academic/artistic)abstract
- Purpose: Health-Related Quality of Life (HR-QoL) among enucleated retinoblastoma (RB) survivors is scarcely studied. Perceptual Visual Dysfunctions (PVDs) are problems concerning interpretation of visual input, that to our knowledge, previously not has been studied in RB patients. This prospective cross-sectional cohort study aim to evaluate HR-QoL and PVDs in RB individuals, treated with ocular prosthesis.Methods: Twenty-seven RB individuals were treated with ocular prosthesis at the Sahlgrenska University Hospital, Gothenburg, Sweden, between 2000-2019. All were invited to the study, 15 (10 females; mean age 15.6 years, range 6.8-27.0 years) accepted. HR-QoL was assessed using the Pediatric Quality of Life inventory (PedsQL) with patients self- and parents-proxy report. Results were compared to normative data. PVDs was examined by history taking covering five areas and results were compared with a healthy, age- and sex- matched control group. Best corrected visual acuity (BCVA) was measured.Results: No differences were found in HR-QoL of individuals with RB compared with healthy controls, between parent proxy compared with parents of healthy children or between individuals with RB and their corresponding parents. More individuals with RB (9/15) reported PVDs in one or more areas (median 1; range 1-4) compared with 1/15 healthy controls; p=0.005 (Fig. 1). Depth perception was the most frequent reported PVD area (n=6), followed by simultaneous perception (n=5), movement (n=2), recognition (n=1) and orientation (n=1). Better HR-QoL correlated with better BCVA (r = -0.68; p=0.01) and fewer affected PVD areas (r = -0.63; p=0.01).Conclusions: The results showed no difference in HR-QoL of the RB individuals or parent-proxy compared with healthy controls. However, enucleated RB survivors were more affected by PVDs than healthy individuals. Their HR-QoL can be negatively affected by having problems within several PVD areas, and BCVA comprise an important role in QoL. It is necessary to identify PVDs to promote the best health care in individuals with RB treated with ocular prothesis. Further research is needed to better understand the impact on QoL and the role of PVDs among these individuals.
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| 5. |
- Edsjö, Anders, et al.
(author)
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Building a precision medicine infrastructure at a national level : The Swedish experience
- 2023
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In: Cambridge Prisms: Precision Medicine. - : Cambridge University Press. - 2752-6143. ; 1
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Research review (peer-reviewed)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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| 6. |
- Lovmar, Lovisa, et al.
(author)
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Genotyping single-nucleotide polymorphisms by minisequencing using tag arrays
- 2005
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In: Microarrays in Clinical Diagnostics. - Totowa, N.J. : Humana Press. - 1588293947 - 9781588293947 ; , s. 79-92
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Book chapter (other academic/artistic)abstract
- The need for large-scale and high-throughput methods for SNP genotyping has rapidly increased during the last decade. Our system, presented here, combines the highly specific genotyping principle of minisequencing with the advantages of a microarray format that allows highly multiplexed and parallel analysis. Cyclic minisequencing reactions with fluorescently labeled dideoxynucleotides (ddNTPs) are performed in solution using multiplex PCR product as template and detection primers, designed to anneal immediately adjacent and upstream of the SNP site. The detection primers carry unique 5' tag sequences and oligonucleotides complementary to the tag sequence, cTags, are immobilized on a microarray. After extension, the tagged detection primers are allowed to hybridize to the cTags; then the fluorescent signals from the array are measured, and the genotypes are deduced according to the label incorporated. The "array of arrays" format of the system, accomplished by a silicon rubber grid giving separate reaction chambers, allows either 80 or 14 samples to be analyzed for up to 200 or 600 SNPs, respectively, on a single microscope slide.
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| 7. |
- Lovmar, Lovisa, 1977-
(author)
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Methods for Analysis of Disease Associated Genomic Sequence Variation
- 2004
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Doctoral thesis (other academic/artistic)abstract
- In Molecular Medicine a wide range of methods are applied to analyze the genome to find genetic predictors of human disease. Apart from predisposing disease, genetic variations may also serve as genetic markers in the search for factors underlying complex diseases. Additionally, they provide a means to distinguish between species, analyze evolutionary relationships and subdivide species into strains. The development and improvement of laboratory techniques and computational methods was a spin-off effect of the Human Genome Project. The same techniques for analyzing genomic sequence variations may be used independent of organism or source of DNA or RNA. In this thesis, methods for high-throughput analysis of sequence variations were developed, evaluated and applied. The performance of several genotyping assays were investigated prior to genotyping 4000 samples in a co-operative genetic epidemiological study. Sequence variations in the estrogen receptor alpha gene were found to be associated with an increased risk of breast and endometrial cancer in Swedish women.Whole genome amplification (WGA) enables large scale genetic analysis of sparse amounts of biobanked DNA samples. The performance of two WGA methods was evaluated using four-color minisequencing on tag-arrays. Our in-house developed assay and “array of arrays” format allow up to 80 samples to be analyzed in parallel on a single microscope slide. Multiple displacement amplification by the Φ29 DNA polymerase gave essentially identical genotyping results as genomic DNA. To facilitate accurate method comparisons, a cluster quality assessment approach was established and applied to assess the performance of four commercially available DNA polymerases in the tag-array minisequencing assay. A microarray method for genotyping human group A rotavirus (HRV) was developed and applied to an epidemiological survey of infectious HRV strains in Nicaragua. The method combines specific capture of amplified viral sequences on microarrays with genotype-specific DNA-polymerase mediated extension of capture oligonucleotides with fluorescent dNTPs.
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| 12. |
- Lovmar, Lovisa, et al.
(author)
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Silhouette scores for assessment of SNP genotype clusters
- 2005
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 6
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Journal article (peer-reviewed)abstract
- Background: High-throughput genotyping of single nucleotide polymorphisms ( SNPs) generates large amounts of data. In many SNP genotyping assays, the genotype assignment is based on scatter plots of signals corresponding to the two SNP alleles. In a robust assay the three clusters that define the genotypes are well separated and the distances between the data points within a cluster are short. "Silhouettes" is a graphical aid for interpretation and validation of data clusters that provides a measure of how well a data point was classified when it was assigned to a cluster. Thus "Silhouettes" can potentially be used as a quality measure for SNP genotyping results and for objective comparison of the performance of SNP assays at different circumstances. Results: We created a program (ClusterA) for calculating "Silhouette scores", and applied it to assess the quality of SNP genotype clusters obtained by single nucleotide primer extension ("minisequencing") in the Tag-microarray format. A Silhouette score condenses the quality of the genotype assignment for each SNP assay into a single numeric value, which ranges from 1.0, when the genotype assignment is unequivocal, down to -1.0, when the genotype assignment has been arbitrary. In the present study we applied Silhouette scores to compare the performance of four DNA polymerases in our minisequencing system by analyzing 26 SNPs in both DNA polarities in 16 DNA samples. We found Silhouettes to provide a relevant measure for the quality of SNP assays at different reaction conditions, illustrated by the four DNA polymerases here. According to our result, the genotypes can be unequivocally assigned without manual inspection when the Silhouette score for a SNP assay is > 0.65. All four DNA polymerases performed satisfactorily in our Tag-array minisequencing system. Conclusion: "Silhouette scores" for assessing the quality of SNP genotyping clusters is convenient for evaluating the quality of SNP genotype assignment, and provides an objective, numeric measure for comparing the performance of SNP assays. The program we created for calculating Silhouette scores is freely available, and can be used for quality assessment of the results from all genotyping systems, where the genotypes are assigned by cluster analysis using scatter plots.
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| 13. |
- Nazaryan-Petersen, Lusine, et al.
(author)
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Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization
- 2018
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In: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 14:11
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Journal article (peer-reviewed)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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| 14. |
- Pettersson, Maria, et al.
(author)
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Cytogenetically visible inversions are formed by multiple molecular mechanisms
- 2020
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In: Human Mutation. - : WILEY. - 1059-7794 .- 1098-1004. ; 41:11, s. 1979-1998
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Journal article (peer-reviewed)abstract
- Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of short-read whole-genome sequencing (WGS), 10X Genomics Chromium WGS, droplet digital polymerase chain reaction and array comparative genomic hybridization we investigated the genomic structure of 18 large unique cytogenetically detected chromosomal inversions and achieved nucleotide resolution of at least one chromosomal inversion junction for 13/18 (72%). Surprisingly, we observed that seemingly copy number neutral inversions can be accompanied by a copy-number gain of up to 350 kb and local genomic complexities (3/18, 17%). In the resolved inversions, the mutational signatures are consistent with nonhomologous end-joining (8/13, 62%) or microhomology-mediated break-induced replication (5/13, 38%). Our study indicates that short-read 30x coverage WGS can detect a substantial fraction of chromosomal inversions. Moreover, replication-based mechanisms are responsible for approximately 38% of those events leading to a significant proportion of inversions that are actually accompanied by additional copy-number variation potentially contributing to the overall phenotypic presentation of those patients.
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| 15. |
- Sandling, Johanna K, 1979-
(author)
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Genetic Analyses of Multiple Sclerosis and Systemic Lupus Erythematosus : From Single Markers to Genome-Wide Data
- 2010
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Doctoral thesis (other academic/artistic)abstract
- In autoimmune diseases an individual’s immune system becomes targeted at the body’s own healthy cells. The aim of this thesis was to identify genetic risk factors for the two autoimmune diseases multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In Study I, we found that genetic variation in the interferon regulatory factor 5 gene (IRF5), previously shown to be associated with SLE, rheumatoid arthritis and inflammatory bowel diseases, was associated also with MS. An insertion/deletion polymorphism in the first intron of IRF5 is as a good functional candidate for this association. IRF5, together with the signal transducer and activator of transcription 4 gene (STAT4), are the most important genetic risk factors for SLE, outside the HLA region. In Study II we showed using a family-based study design that genetic variation in STAT4 is associated with SLE also in the Finnish population. In Study III, we investigated a STAT4 risk allele for SLE for its association with cardiovascular disease in SLE patients. The risk allele of STAT4 proved to be strongly associated with ischemic cerebrovascular disease and anti-phospholipid antibodies in SLE patients. A possible mechanism for this association is that the risk allele leads to increased production of pro-thrombotic anti-phospholipid antibodies, which in turn increases the risk for stroke. Both IRF5 and STAT4 are involved in signalling of the type I interferon system. In Study IV, we investigated 78 additional genes in this system for their association with SLE in a Swedish cohort. The most promising results were followed up in additional patients and controls from Sweden and the US. Two novel SLE genes were identified. In Study V a large follow-up of a genome-wide association study was performed. Five new SLE loci were identified: TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10. A number of genes previously shown to be associated with other autoimmune diseases were also tested for association with SLE. This analysis identified the type I interferon system gene IFIH1 as a novel SLE risk locus. These studies confirms the central role of the type I interferon system in SLE and further suggests common genetic risk factors in autoimmunity.
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| 17. |
- Topa, Alexandra, 1978, et al.
(author)
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On the significance of craniosynostosis in a case of Kabuki syndrome with a concomitant KMT2D mutation and 3.2 Mbp de novo 10q22.3q23.1 deletion
- 2017
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In: American Journal of Medical Genetics Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 173:8, s. 2219-2225
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Journal article (peer-reviewed)abstract
- Craniosynostosis has rarely been described in patients with Kabuki syndrome. We report here a boy with facial asymmetry due to combined premature synostosis of the right coronal and sagittal sutures as well as several symptoms reminiscent of Kabuki syndrome (KS). Our case supports previous observations and suggests that craniosynostosis is a part of the KS phenotype. The uniqueness of our case is the sporadic co-occurrence of two genetic disorders, that is, a de novo frameshift variant in the KMT2D gene and a de novo 3.2 Mbp 10q22.3q23.1 deletion. Our findings emphasize the importance of the initial clinical assessment of children with craniosynostosis and that genomic and monogenic disorders, such as Kabuki syndrome, should be considered among the differential diagnoses of syndromic forms of craniosynostosis.
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| 18. |
- Topa, Alexandra, 1978, et al.
(author)
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The value of genome-wide analysis in craniosynostosis
- 2024
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In: FRONTIERS IN GENETICS. - 1664-8021. ; 14
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Journal article (peer-reviewed)abstract
- Background: This study assessed the diagnostic yield of high-throughput sequencing methods in a cohort of craniosynostosis (CS) patients not presenting causal variants identified through previous targeted analysis.Methods: Whole-genome or whole-exome sequencing (WGS/WES) was performed in a cohort of 59 patients (from 57 families) assessed by retrospective phenotyping as having syndromic or nonsyndromic CS.Results: A syndromic form was identified in 51% of the unrelated cases. A genetic cause was identified in 38% of syndromic cases, with novel variants detected in FGFR2 (a rare Alu insertion), TWIST1, TCF12, KIAA0586, HDAC9, FOXP1, and NSD2. Additionally, we report two patients with rare recurrent variants in KAT6A and YY1 as well as two patients with structural genomic aberrations: one with a 22q13 duplication and one with a complex rearrangement involving chromosome 2 (2p25 duplication including SOX11 and deletion of 2q22). Moreover, we identified potentially relevant variants in 87% of the remaining families with no previously detected causal variants, including novel variants in ADAMTSL4, ASH1L, ATRX, C2CD3, CHD5, ERF, H4C5, IFT122, IFT140, KDM6B, KMT2D, LTBP1, MAP3K7, NOTCH2, NSD1, SOS1, SPRY1, POLR2A, PRRX1, RECQL4, TAB2, TAOK1, TET3, TGFBR1, TCF20, and ZBTB20.Conclusion: These results confirm WGS/WES as a powerful diagnostic tool capable of either targeted in silico or broad genomic analysis depending on phenotypic presentation (e.g., classical or unusual forms of syndromic CS).
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| 19. |
- Wedrén, Sara, et al.
(author)
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Estrogen receptor alpha gene polymorphism and endometrial cancer risk : a case-control study
- 2008
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 8, s. 322-
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Journal article (peer-reviewed)abstract
- BACKGROUND: Estrogen is an established endometrial carcinogen. One of the most important mediators of estrogenic action is the estrogen receptor alpha. We have investigated whether polymorphic variation in the estrogen receptor alpha gene (ESR1) is associated with endometrial cancer risk. METHODS: In 702 cases with invasive endometrial cancer and 1563 controls, we genotyped five markers in ESR1 and used logistic regression models to estimate odds ratios (OR) and 95 percent confidence intervals (CI). RESULTS: We found an association between rs2234670, rs2234693, as well as rs9340799, markers in strong linkage disequilibrium (LD), and endometrial cancer risk. The association with rs9340799 was the strongest, OR 0.75 (CI 0.60-0.93) for heterozygous and OR 0.53 (CI 0.37-0.77) for homozygous rare compared to those homozygous for the most common allele. Haplotype models did not fit better to the data than single marker models. CONCLUSION: We found that intronic variation in ESR1 was associated with endometrial cancer risk.
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| 20. |
- Wedrén, Sara, et al.
(author)
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Oestrogen receptor alpha gene haplotype and postmenopausal breast cancer risk : a case control study
- 2004
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 6:4, s. R437-49
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Journal article (other academic/artistic)abstract
- INTRODUCTION: Oestrogen receptor alpha, which mediates the effect of oestrogen in target tissues, is genetically polymorphic. Because breast cancer development is dependent on oestrogenic influence, we have investigated whether polymorphisms in the oestrogen receptor alpha gene (ESR1) are associated with breast cancer risk. METHODS: We genotyped breast cancer cases and age-matched population controls for one microsatellite marker and four single-nucleotide polymorphisms (SNPs) in ESR1. The numbers of genotyped cases and controls for each marker were as follows: TAn, 1514 cases and 1514 controls; c.454-397C --> T, 1557 cases and 1512 controls; c.454-351A --> G, 1556 cases and 1512 controls; c.729C --> T, 1562 cases and 1513 controls; c.975C --> G, 1562 cases and 1513 controls. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Haplotype effects were estimated in an exploratory analysis, using expectation-maximisation algorithms for case-control study data. RESULTS: There were no compelling associations between single polymorphic loci and breast cancer risk. In haplotype analyses, a common haplotype of the c.454-351A --> G or c.454-397C --> T and c.975C --> G SNPs appeared to be associated with an increased risk for ductal breast cancer: one copy of the c.454-351A --> G and c.975C --> G haplotype entailed an OR of 1.19 (95% CI 1.06-1.33) and two copies with an OR of 1.42 (95% CI 1.15-1.77), compared with no copies, under a model of multiplicative penetrance. The association with the c.454-397C --> T and c.975C --> G haplotypes was similar. Our data indicated that these haplotypes were more influential in women with a high body mass index. Adjustment for multiple comparisons rendered the associations statistically non-significant. CONCLUSION: We found suggestions of an association between common haplotypes in ESR1 and the risk for ductal breast cancer that is stronger in heavy women.
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