Nanopore long-read sequencing facilitates accurate diagnosis of KMT2B-related dystonia

Diagnosis of KMT2B-related dystonia remains challenging due to the high prevalence of variants of uncertain significance and technological constraint of short-read pipelines. To overcome these limitations, we integrated nanopore-based long-read sequencing with a validated KMT2B-episignature classifier to perform simultaneous genetic and epigenetic profiling for three cases with prior uncertain KMT2B-related findings. Our workflow detected characteristic deviations in the KMT2B-episignature score in two cases with previously unresolved or missed KMT2B variants, while refuting an ambiguous indel call. Combining genomic-variant detection with DNA-methylation analysis eliminated the need for sequential testing and enhanced accurate diagnosis of KMT2B-related dystonia, offering a basis for streamlined epigenetics-guided diagnostics.

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Publication Details

Journal
Clinical Epigenetics
Published
2026-09-17
DOI
https://doi.org/10.1186/s13148-026-02243-5
Primary Topic
Genomics and Rare Diseases
Type
article
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article

Nanopore long-read sequencing facilitates accurate diagnosis of KMT2B-related dystonia

Fatemeh Peymani, Michael Zech, Petra Havránková, Erik Tilch et al.
Clinical Epigenetics
Genomics and Rare Diseases
article

Nanopore long-read sequencing facilitates accurate diagnosis of KMT2B-related dystonia

Fatemeh Peymani, Michael Zech, Petra Havránková, Erik Tilch, Holger Prokisch, Ugo Sorrentino, Konrad Oexle, Tereza Serranová, Nazanin Mirza‐Schreiber, Martin Pavlov, Sandy Lösecke, Juliane Winkelmann, Sylvia Boesch, Sebastian Eck, Elisabeth Graf, Robert Jech, Lukas Kunc, Elisabetta Indelicato
article en

Abstract

Diagnosis of KMT2B-related dystonia remains challenging due to the high prevalence of variants of uncertain significance and technological constraint of short-read pipelines. To overcome these limitations, we integrated nanopore-based long-read sequencing with a validated KMT2B-episignature classifier to perform simultaneous genetic and epigenetic profiling for three cases with prior uncertain KMT2B-related findings. Our workflow detected characteristic deviations in the KMT2B-episignature score in two cases with previously unresolved or missed KMT2B variants, while refuting an ambiguous indel call. Combining genomic-variant detection with DNA-methylation analysis eliminated the need for sequential testing and enhanced accurate diagnosis of KMT2B-related dystonia, offering a basis for streamlined epigenetics-guided diagnostics.

Clinical EpigeneticsVol. 18(1)
Innsbruck Medical University (AT), Charles University (CZ), Helmholtz Zentrum München (DE), German Center for Pediatric and Adolescent Rheumatology (DE), Munich Cluster for Systems Neurology (DE), Institute of Human Genetics (PL), Deutsches Jugendinstitut (DE), Medizinische Zentrum für Gesundheit (DE), General University Hospital in Prague (CZ), Technical University of Munich (DE)
Openalex Percentile: Top 12%
Genomics and Rare Diseases
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