| 1. |
- Ali, Heidi, et al.
(författare)
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Classification of mismatch repair gene missense variants with PON-MMR
- 2012
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 33:4, s. 642-650
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Tidskriftsartikel (refereegranskat)abstract
- Numerous mismatch repair (MMR) gene variants have been identified in Lynch syndrome and other cancer patients, but knowledge about their pathogenicity is frequently missing. The diagnosis and treatment of patients would benefit from knowing which variants are disease related. Bioinformatic approaches are well suited to the problem and can handle large numbers of cases. Functional effects were revealed based on literature for 168 MMR missense variants. Performance of numerous prediction methods was tested with this dataset. Among the tested tools, only the results of tolerance prediction methods correlated to functional information, however, with poor performance. Therefore, a novel consensus-based predictor was developed. The novel prediction method, pathogenic-or-not mismatch repair (PON-MMR), achieved accuracy of 0.87 and Matthews correlation coefficient of 0.77 on the experimentally verified variants. When applied to 616 MMR cases with unknown effects, 81 missense variants were predicted to be pathogenic and 167 neutral. With PON-MMR, the number of MMR missense variants with unknown effect was reduced by classifying a large number of cases as likely pathogenic or benign. The results can be used, for example, to prioritize cases for experimental studies and assist in the classification of cases. Hum Mutat 33:642650, 2012. (c) 2012 Wiley Periodicals, Inc.
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| 2. |
- Ali, Heidi, et al.
(författare)
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Performance of Protein Disorder Prediction Programs on Amino Acid Substitutions
- 2014
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 35:7, s. 794-804
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Forskningsöversikt (refereegranskat)abstract
- Many proteins contain intrinsically disordered regions, which may be crucial for function, but on the other hand be related to the pathogenicity of variants. Prediction programs have been developed to detect disordered regions from sequences and used to predict the consequences of variants, although their performance for this task has not been assessed. We tested the performance of protein disorder prediction programs in detecting changes to disorder caused by amino acid substitutions. We assessed the performance of 29 protein disorder predictors and versions with 101 amino acid substitutions, whose effects have been experimentally validated. Disorder predictors detected the true positives at most with 6% success rate and true negatives with 34% rate for variants. The corresponding rates for the wild-type forms are 7% and 90%, respectively. The analysis revealed that disorder programs cannot reliably predict the effects of substitutions; consequently, the tested methods, and possibly similar programs, cannot be recommended for variant analysis without other information indicating to the relevance of disorder. These results inspired us to develop a new method, PON-Diso (http://structure.bmc.lu.se/PON-Diso), for disorder-related amino acid substitutions. With 50% success rate for independent test set and 70.5% rate in cross-validation, it outperforms the evaluated methods.
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| 3. |
- Andersson, Nadine G, et al.
(författare)
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Novel F8 and F9 gene variants from the PedNet Hemophilia Registry classified according to ACMG/AMP guidelines
- 2020
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 41:12, s. 2058-2072
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Tidskriftsartikel (refereegranskat)abstract
- In hemophilia A and B, analysis of the F8 and F9 gene variants enables carrier- and prenatal diagnosis and prediction of risk for development of inhibitors. The PedNet Registry collects clinical, genetic and phenotypic data prospectively on >2000 children with hemophilia. The genetic reports of F8/F9 gene variants were classified uniformly to HGVS nomenclature and re-evaluated using international population- and disease-specific databases, literature survey and, where applicable, computational predictive programs. We report 88 novel variants in the F8 and F9 genes, 80 fulfilling criteria for class 5 (pathogenic), six for class 4 (likely pathogenic) and two fulfilling criteria for class 3 (variant of unknown significance) of the ACMG (American College of Medical Genetics and Genomics)/AMP (Association for Molecular Pathology) guidelines together with information on the respective phenotype and inhibitor formation. The study highlights the need to re-evaluate and update earlier genetic reports in hemophilia both locally but also in variant databases in the light of changed nomenclature and new guidelines. This article is protected by copyright. All rights reserved.
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| 4. |
- Borg, Åke, et al.
(författare)
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Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
- 2010
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 31, s. 1200-1240
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Tidskriftsartikel (refereegranskat)abstract
- BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC. (c) 2010 Wiley-Liss, Inc.
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| 5. |
- Carraro, Marco, et al.
(författare)
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Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI
- 2017
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 38:9, s. 1042-1050
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Tidskriftsartikel (refereegranskat)abstract
- Correct phenotypic interpretation of variants of unknown significance for cancer-associated genes is a diagnostic challenge as genetic screenings gain in popularity in the next-generation sequencing era. The Critical Assessment of Genome Interpretation (CAGI) experiment aims to test and define the state of the art of genotype-phenotype interpretation. Here, we present the assessment of the CAGI p16INK4a challenge. Participants were asked to predict the effect on cellular proliferation of 10 variants for the p16INK4a tumor suppressor, a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene. Twenty-two pathogenicity predictors were assessed with a variety of accuracy measures for reliability in a medical context. Different assessment measures were combined in an overall ranking to provide more robust results. The R scripts used for assessment are publicly available from a GitHub repository for future use in similar assessment exercises. Despite a limited test-set size, our findings show a variety of results, with some methods performing significantly better. Methods combining different strategies frequently outperform simpler approaches. The best predictor, Yang&Zhou lab, uses a machine learning method combining an empirical energy function measuring protein stability with an evolutionary conservation term. The p16INK4a challenge highlights how subtle structural effects can neutralize otherwise deleterious variants.
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| 6. |
- Charbonnier, FC, et al.
(författare)
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The 5 ' Region of the MSH2 gene involved in hereditary non-polyposis colorectal cancer contains a high density of recombinogenic sequences
- 2005
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 26:3, s. 255-261
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Tidskriftsartikel (refereegranskat)abstract
- MSH2 rearrangements are involved in approximately 10% of hereditary non,polyposis colorectal cancer (HNPCC) families, and in most of the rearrangements, exon I is deleted. We scanned by quantitative multiplex polymerase chain reaction (PCR) of short fluorescent fragments (QMPSF) 200 kb of genomic sequences upstream of the MSH2 transcription initiation site in 21 HNPCC families with exon I deletions. This QMPSF scan revealed 12 distinct 5' breakpoints located up to 200 kb upstream of the MSH2 transcription initiation site. Sequencing analysis of the rearranged allele in 17 families revealed that most of the deletions (15/17) resulted from homologous Alu-mediated recombination. QMPSF and sequencing analysis in these 21 families led us to detect the presence of 20 distinct 5' breakpoints. In 14 out of 15 Alu-mediated recombinations, we found, either within the identical region in which the recombination had probably occurred or in its vicinity, the 26,bp Alu core sequence containing the recombinogenic Chi-like motif. Compared to the equivalent regions of other human genes, the MSH2 upstream region was found to contain a high density of Alu repeats (30% within 228 kb and 43% within 50 kb), most of which belong to the old Alu S subfamilies. In conclusion, this study demonstrates the heterogeneity of the breakpoints within the MSH2 upstream region and reveals the remarkable density of recombinogenic Alu sequences in this region.
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| 7. |
- Clendenning, M, et al.
(författare)
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Long-range PCR facilitates the identification of PMS2-specific mutations
- 2006
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 27:5, s. 490-495
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Tidskriftsartikel (refereegranskat)abstract
- Mutations within the DNA mismatch repair gene, "postmeiotic segregation increased 2" (PMS2), have been associated with a predisposition to hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome). The presence of a large family of highly homologous PMS2 pseudogenes has made previous attempts to sequence PMS2 very difficult. Here, we describe a novel method that utilizes long-range PCR as a way to preferentially amplify PMS2 and not the pseudogenes. A second, exon-specific, amplification from diluted long-range products enables us to obtain a clean sequence that shows no evidence of pseudogene contamination. This method has been used to screen a cohort of patients whose tumors were negative for the PMS2 protein by immunohistochemistry and had not shown any mutations within the MLH1 gene. Sequencing of the PMS2 gene from 30 colorectal and I I endometrial cancer patients identified 10 novel sequence changes as well as 17 sequence changes that had previously been identified. In total, putative pathologic mutations were detected in 11 of the 41 families. Among these were five novel mutations, c.705+1G > T, c.736-741del6ins11, c.862_863del, c.1688G > T, and c.2007-IG > A. We conclude that PMS2 mutation detection in selected Lynch syndrome and Lynch syndrome-like patients is both feasible and desirable.
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| 8. |
- Daneshjou, Roxana, et al.
(författare)
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Working toward precision medicine : Predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges
- 2017
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 38:9, s. 1182-1192
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Tidskriftsartikel (refereegranskat)abstract
- Precision medicine aims to predict a patient's disease risk and best therapeutic options by using that individual's genetic sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype-phenotype prediction challenges; participants build models, undergo assessment, and share key findings. For CAGI 4, three challenges involved using exome-sequencing data: Crohn's disease, bipolar disorder, and warfarin dosing. Previous CAGI challenges included prior versions of the Crohn's disease challenge. Here, we discuss the range of techniques used for phenotype prediction as well as the methods used for assessing predictive models. Additionally, we outline some of the difficulties associated with making predictions and evaluating them. The lessons learned from the exome challenges can be applied to both research and clinical efforts to improve phenotype prediction from genotype. In addition, these challenges serve as a vehicle for sharing clinical and research exome data in a secure manner with scientists who have a broad range of expertise, contributing to a collaborative effort to advance our understanding of genotype-phenotype relationships.
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| 9. |
- Ekong, Rosemary, et al.
(författare)
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Checklist for gene/disease-specific variation database curators to enable ethical data management
- 2019
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 40:10, s. 1634-1640
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Tidskriftsartikel (refereegranskat)abstract
- Databases with variant and phenotype information are essential for advancing research and improving the health and welfare of individuals. These resources require data to be collected, curated, and shared among relevant specialties to maximize impact. The increasing generation of data which must be shared both nationally and globally for maximal effect presents important ethical and privacy concerns. Database curators need to ensure that their work conform to acceptable ethical standards. A Working Group of the Human Variome Project had the task of updating and streamlining ethical guidelines for locus-specific/gene variant database curators. In this article, we present practical and achievable steps which should assist database curators in carrying out their responsibilities within acceptable ethical norms.
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| 10. |
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