> Detailanzeige

Oexle, Konrad; Zech, Michael; Stühn, Lara G.; Siegert, Sandy; Brunet, Theresa; Schmidt, Wolfgang M.; Wagner, Matias; Schmidt, Axel; Engels, Hartmut; Tilch, Erik; Monestier, Olivier; Destrėe, Anne; Hanker, Britta; Boesch, Sylvia; Jech, Robert; Berutti, Riccardo; Kaiser, Frank; Haslinger, Bernhard; Haack, Tobias B.; Garavaglia, Barbara; Krawitz, Peter; Winkelmann, Juliane; Mirza-Schreiber, Nazanin

Episignature analysis of moderate effects and mosaics

Literatur-
verwaltung

Zur
Merkliste

Lösche von
Merkliste

Per Whatsapp teilen

Schließen

Merkliste



Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
  • Medientyp: E-Artikel
  • Titel: Episignature analysis of moderate effects and mosaics
  • Beteiligte: Oexle, Konrad; Zech, Michael; Stühn, Lara G.; Siegert, Sandy; Brunet, Theresa; Schmidt, Wolfgang M.; Wagner, Matias; Schmidt, Axel; Engels, Hartmut; Tilch, Erik; Monestier, Olivier; Destrėe, Anne; Hanker, Britta; Boesch, Sylvia; Jech, Robert; Berutti, Riccardo; Kaiser, Frank; Haslinger, Bernhard; Haack, Tobias B.; Garavaglia, Barbara; Krawitz, Peter; Winkelmann, Juliane; Mirza-Schreiber, Nazanin
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: European Journal of Human Genetics
  • Sprache: Englisch
  • DOI: 10.1038/s41431-023-01406-9
  • ISSN: 1018-4813; 1476-5438
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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<jats:italic>KMT2B</jats:italic>-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<jats:italic>KMT2D</jats:italic>-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.</jats:p>