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Oexle, K. ; Zech, M. ; Stühn, L.G.* ; Siegert, S.* ; Brunet, T.* ; Schmidt, W.M.* ; Wagner, M.* ; Schmidt, A.* ; Engels, H.* ; Tilch, E. ; Monestier, O.* ; Destrée, A.* ; Hanker, B.* ; Boesch, S.* ; Jech, R.* ; Berutti, R. ; Kaiser, F.* ; Haslinger, B.* ; Haack, T.B.* ; Garavaglia, B.* ; Krawitz, P.* ; Winkelmann, J. ; Mirza-Schreiber, N.

Episignature analysis of moderate effects and mosaics.

Eur. J. Hum. Genet. 31, 1032-1039 (2023)
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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. [Figure not available: see fulltext.].
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dna Methylation Signature; Variants; Package
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 1018-4813
e-ISSN 1476-5438
Journal European Journal of Human Genetics
Quellenangaben Volume: 31, Issue: 9, Pages: 1032-1039 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
G-503292-001
Grants Helmholtz HIP
Deutsche Forschungsgemeinschaft (DFG)
DOI 10.1038/s41431-023-01406-9
WOS ID 001020337300001
Scopus ID 85162855988
PubMed ID 37365401
Erfassungsdatum 2023-10-18
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