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Episignature analysis of moderate effects and mosaics
K. Oexle, M. Zech, LG. Stühn, S. Siegert, T. Brunet, WM. Schmidt, M. Wagner, A. Schmidt, H. Engels, E. Tilch, O. Monestier, A. Destrėe, B. Hanker, S. Boesch, R. Jech, R. Berutti, F. Kaiser, B. Haslinger, TB. Haack, B. Garavaglia, P. Krawitz, J....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
NLK
Free Medical Journals
od 2009
PubMed Central
od 2009 do Před 1 rokem
Europe PubMed Central
od 2009 do Před 1 rokem
ProQuest Central
od 2000-01-01 do Před 1 rokem
Open Access Digital Library
od 1998-01-01
Health & Medicine (ProQuest)
od 2000-01-01 do Před 1 rokem
- MeSH
- alely MeSH
- fenotyp MeSH
- lidé MeSH
- metylace DNA * MeSH
- mnohočetné abnormality * genetika MeSH
- mozaicismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
DNA methylation classifiers ("episignatures") help to determine the pathogenicity of variants of uncertain significance (VUS). However, their sensitivity is limited due to their training on unambiguous cases with strong-effect variants so that the classification of variants with reduced effect size or in mosaic state may fail. Moreover, episignature evaluation of mosaics as a function of their degree of mosaicism has not been developed so far. We improved episignatures with respect to three categories. Applying (i) minimum-redundancy-maximum-relevance feature selection we reduced their length by up to one order of magnitude without loss of accuracy. Performing (ii) repeated re-training of a support vector machine classifier by step-wise inclusion of cases in the training set that reached probability scores larger than 0.5, we increased the sensitivity of the episignature-classifiers by 30%. In the newly diagnosed patients we confirmed the association between DNA methylation aberration and age at onset of KMT2B-deficient dystonia. Moreover, we found evidence for allelic series, including KMT2B-variants with moderate effects and comparatively mild phenotypes such as late-onset focal dystonia. Retrained classifiers also can detect mosaics that previously remained below the 0.5-threshold, as we showed for KMT2D-associated Kabuki syndrome. Conversely, episignature-classifiers are able to revoke erroneous exome calls of mosaicism, as we demonstrated by (iii) comparing presumed mosaic cases with a distribution of artificial in silico-mosaics that represented all the possible variation in degree of mosaicism, variant read sampling and methylation analysis.
Centre de Génétique Humaine Institut de Pathologie et de Génétique ASBL 6041 Gosselies Belgium
Centre for Rare Diseases University of Tuebingen 72076 Tuebingen Germany
Chair of Neurogenetics Technical University of Munich School of Medicine 81675 Munich Germany
Department of Neurology Medizinische Universität 6020 Insbruck Austria
Department of Neurology Technical University of Munich School of Medicine 81675 Munich Germany
Department of Pediatric and Adolescent Medicine Medical University of Vienna 1090 Wien Austria
Fondazione IRCCS Istituto Neurologico Carlo Besta 20133 Milano Italy
Institute for Genomic Statistics and Bioinformatics Universität Bonn 53127 Bonn Germany
Institute of Human Genetics School of Medicine University Hospital Bonn 53127 Bonn Germany
Institute of Human Genetics Technical University of Munich School of Medicine 81675 Munich Germany
Institute of Human Genetics Universitätsklinikum Essen 45122 Essen Germany
Institute of Human Genetics Universitätsklinikum Schleswig Holstein 23538 Lübeck Germany
Institute of Medical Genetics and Applied Genomics University of Tuebingen 72076 Tübingen Germany
Institute of Neurogenomics Helmholtz Munich 85764 Neuherberg Germany
Citace poskytuje Crossref.org
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