| 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. |
- Aspatwar, Ashok, et al.
(författare)
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Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:3, s. 417-432
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Tidskriftsartikel (refereegranskat)abstract
- Congenital ataxia and mental retardation are mainly caused by variations in the genes that affect brain development. Recent reports have shown that mutations in the CA8 gene are associated with mental retardation and ataxia in humans and ataxia in mice. The gene product, carbonic anhydrase-related protein VIII (CARP VIII), is predominantly present in cerebellar Purkinje cells, where it interacts with the inositol 1,4,5-trisphosphate receptor type 1, a calcium channel. In this study, we investigated the effects of the loss of function of CARP VIII during embryonic development in zebrafish using antisense morpholino oligonucleotides against the CA8 gene. Knockdown of CA8 in zebrafish larvae resulted in a curved body axis, pericardial edema and abnormal movement patterns. Histologic examination revealed gross morphologic defects in the cerebellar region and in the muscle. Electron microscopy studies showed increased neuronal cell death in developing larvae injected with CA8 antisense morpholinos. These data suggest a pivotal role for CARP VIII during embryonic development. Furthermore, suppression of CA8 expression leads to defects in motor and coordination functions, mimicking the ataxic human phenotype. This work reveals an evolutionarily conserved function of CARP VIII in brain development and introduces a novel zebrafish model in which to investigate the mechanisms of CARP VIII-related ataxia and mental retardation in humans.
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| 4. |
- Byrne, Myles, et al.
(författare)
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VarioML framework for comprehensive variation data representation and exchange
- 2012
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 13:254
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sharing of data about variation and the associated phenotypes is a critical need, yet variant information can be arbitrarily complex, making a single standard vocabulary elusive and re-formatting difficult. Complex standards have proven too time-consuming to implement. Results: The GEN2PHEN project addressed these difficulties by developing a comprehensive data model for capturing biomedical observations, Observ-OM, and building the VarioML format around it. VarioML pairs a simplified open specification for describing variants, with a toolkit for adapting the specification into one's own research workflow. Straightforward variant data can be captured, federated, and exchanged with no overhead; more complex data can be described, without loss of compatibility. The open specification enables push-button submission to gene variant databases (LSDBs) e. g., the Leiden Open Variation Database, using the Cafe Variome data publishing service, while VarioML bidirectionally transforms data between XML and web-application code formats, opening up new possibilities for open source web applications building on shared data. A Java implementation toolkit makes VarioML easily integrated into biomedical applications. VarioML is designed primarily for LSDB data submission and transfer scenarios, but can also be used as a standard variation data format for JSON and XML document databases and user interface components. Conclusions: VarioML is a set of tools and practices improving the availability, quality, and comprehensibility of human variation information. It enables researchers, diagnostic laboratories, and clinics to share that information with ease, clarity, and without ambiguity.
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| 5. |
- Ekvall, Sara, 1982-, et al.
(författare)
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Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome
- 2014
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Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 164:3, s. 579-587
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Tidskriftsartikel (refereegranskat)abstract
- Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present.
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| 6. |
- Kuusisto, Kirsi M., et al.
(författare)
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Copy Number Variation Analysis in Familial BRCA1/2-Negative Finnish Breast and Ovarian Cancer
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Inherited factors predisposing individuals to breast and ovarian cancer are largely unidentified in a majority of families with hereditary breast and ovarian cancer (HBOC). We aimed to identify germline copy number variations (CNVs) contributing to HBOC susceptibility in the Finnish population. Methods: A cohort of 84 HBOC individuals (negative for BRCA1/2-founder mutations and pre-screened for the most common breast cancer genes) and 36 healthy controls were analysed with a genome-wide SNP array. CNV-affecting genes were further studied by Gene Ontology term enrichment, pathway analyses, and database searches to reveal genes with potential for breast and ovarian cancer predisposition. CNVs that were considered to be important were validated and genotyped in 20 additional HBOC individuals (6 CNVs) and in additional healthy controls (5 CNVs) by qPCR. Results: An intronic deletion in the EPHA3 receptor tyrosine kinase was enriched in HBOC individuals (12 of 101, 11.9%) compared with controls (27 of 432, 6.3%) (OR = 1.96; P = 0.055). EPHA3 was identified in several enriched molecular functions including receptor activity. Both a novel intronic deletion in the CSMD1 tumor suppressor gene and a homozygous intergenic deletion at 5q15 were identified in 1 of 101 (1.0%) HBOC individuals but were very rare (1 of 436, 0.2% and 1 of 899, 0.1%, respectively) in healthy controls suggesting that these variants confer disease susceptibility. Conclusion: This study reveals new information regarding the germline CNVs that likely contribute to HBOC susceptibility in Finland. This information may be used to facilitate the genetic counselling of HBOC individuals but the preliminary results warrant additional studies of a larger study group.
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| 7. |
- Nair, Preethy Sasidharan, et al.
(författare)
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VariBench: A Benchmark Database for Variations
- 2013
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 34:1, s. 42-49
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Tidskriftsartikel (refereegranskat)abstract
- Several computational methods have been developed for predicting the effects of rapidly expanding variation data. Comparison of the performance of tools has been very difficult as the methods have been trained and tested with different datasets. Until now, unbiased and representative benchmark datasets have been missing. We have developed a benchmark database suite, VariBench, to overcome this problem. VariBench contains datasets of experimentally verified high-quality variation data carefully chosen from literature and relevant databases. It provides the mapping of variation position to different levels (protein, RNA and DNA sequences, protein three-dimensional structure), along with identifier mapping to relevant databases. VariBench contains the first benchmark datasets for variation effect analysis, a field which is of high importance and where many developments are currently going on. VariBench datasets can be used, for example, to test performance of prediction tools as well as to train novel machine learning-based tools. New datasets will be included and the community is encouraged to submit high-quality datasets to the service. VariBench is freely available at http://structure.bmc.lu.se/VariBench. Hum Mutat 34:42-49, 2013. (C) 2012 Wiley Periodicals, Inc.
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| 8. |
- Olatubosun, Ayodeji, et al.
(författare)
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PON-P: Integrated Predictor for Pathogenicity of Missense Variants
- 2012
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 33:8, s. 1166-1174
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Tidskriftsartikel (refereegranskat)abstract
- High-throughput sequencing data generation demands the development of methods for interpreting the effects of genomic variants. Numerous computational methods have been developed to assess the impact of variations because experimental methods are unable to cope with both the speed and volume of data generation. To harness the strength of currently available predictors, the Pathogenic-or-Not-Pipeline (PON-P) integrates five predictors to predict the probability that nonsynonymous variations affect protein function and may consequently be disease related. Random forest methodology-based PON-P shows consistently improved performance in cross-validation tests and on independent test sets, providing ternary classification and statistical reliability estimate of results. Applied to missense variants in a melanoma cancer cell line, PON-P predicts variants in 17 genes to affect protein function. Previous studies implicate nine of these genes in the pathogenesis of various forms of cancer. PON-P may thus be used as a first step in screening and prioritizing variants to determine deleterious ones for further experimentation. Hum Mutat 33:1166-1174, 2012. (c) 2012 Wiley Periodicals, Inc.
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| 9. |
- Ortutay, Csaba, et al.
(författare)
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Conserved and Quickly Evolving Immunome Genes Have Different Evolutionary Paths
- 2012
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 33:10, s. 1456-1463
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Tidskriftsartikel (refereegranskat)abstract
- Genetic, transcript, and protein level variations have important functional and evolutionary consequences. We performed systematic data collection and analysis of copy-number variations, single-nucleotide polymorphisms, disease-causing variations, messenger RNA splicing variants, and protein posttranslational modifications for the genes and proteins essential for human immune system. Information about polymorphic and evolutionarily fixed genetic variations was used to group immunome genes to the most conserved and the most quickly changing ones under directed selection during the recent immunome evolution. Gene Ontology terms related to adaptive immunity are associated with gene groups subject to recent directing selection. In addition, several other characteristics of the immunome genes and proteins in these two categories have statistically significant differences. The presented findings question the usability of directed mouse genes as models for human diseases and conditions and shed light on the fine tuning of human immunity and its diverse functions. HumMutat 33:1456-1463, 2012. (C) 2012 Wiley Periodicals, Inc.
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| 10. |
- Patrinos, George P., et al.
(författare)
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Human variome project country nodes: Documenting genetic information within a country
- 2012
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 33:11, s. 1513-1519
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Tidskriftsartikel (refereegranskat)abstract
- The Human Variome Project (http://www.humanvariomeproject.org) is an international effort aiming to systematically collect and share information on all human genetic variation. The two main pillars of this effort are gene/disease-specific databases and a network of Human Variome Project Country Nodes. The latter are nationwide efforts to document the genomic variation reported within a specific population. The development and successful operation of the Human Variome Project Country Nodes are of utmost importance to the success of Human Variome Project's aims and goals because they not only allow the genetic burden of disease to be quantified in different countries, but also provide diagnosticians and researchers access to an up-to-date resource that will assist them in their daily clinical practice and biomedical research, respectively. Here, we report the discussions and recommendations that resulted from the inaugural meeting of the International Confederation of Countries Advisory Council, held on 12th December 2011, during the 2011 Human Variome Project Beijing Meeting. We discuss the steps necessary to maximize the impact of the Country Node effort for developing regional and country-specific clinical genetics resources and summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects. Hum Mutat 33:15131519, 2012. (c) 2012 Wiley Periodicals, Inc.
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