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