ArticleEuropean journal of human genetics : EJHG2023
Episignature analysis of moderate effects and mosaics.
Article in European journal of human genetics : EJHG, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Clinical Epigenomics in Rare Diseases: Interpreting DNA Methylation Episignatures.Molecular genetics & genomic medicine · 2026Review
- Nanopore long-read sequencing facilitates accurate diagnosis of KMT2B-related dystonia.Clinical epigenetics · 2026Article
- Review
- Analysis Methods for Diagnosing Rare Neurodevelopmental Diseases with Episignatures: A Systematic Review of the Literature.Biomedicines · 2025Review
- Long-Read Sequencing: The Third Generation of Diagnostic Testing for Dystonia.Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Clinical evaluation of long-read sequencing-based episignature detection in developmental disorders.Genome medicine · 2025Article
- Nanopore sequencing enables combined detection ofFrontiers in genetics · 2025Article
- Expanding Upon Genomics in Rare Diseases: Epigenomic Insights.International journal of molecular sciences · 2024Review
- Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool.Clinical epigenetics · 2024Article
- DNA methylation profiling in Kabuki syndrome: reclassification of germline KMT2D VUS and sensitivity in validating postzygotic mosaicism.European journal of human genetics : EJHG · 2024Article
- Chromatinopathies: insight in clinical aspects and underlying epigenetic changes.Journal of applied genetics · 2024Review
- 2023 in the European Journal of Human Genetics.European journal of human genetics : EJHG · 2024Article
- Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders.European journal of human genetics : EJHG · 2024Article
- Are there two disjunct episignatures for KMT2B-related disease?Brain communications · 2024Article
- Why don't we all use genomic testing?European journal of human genetics : EJHG · 2023Article
- Article
Corrections and comments
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Authors and funding
23 authors.
Funding
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Abstract
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.
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