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

KMT2B

Nanopore long-read sequencing combined with a validated KMT2B episignature classifier for simultaneous genetic and epigenetic profiling

Diagnosing KMT2B-related dystonia remains difficult because of the high prevalence of variants of uncertain significance and the technical limits of short-read pipelines. The authors combined nanopore long-read sequencing with a validated KMT2B episignature classifier to perform simultaneous genetic and epigenetic profiling in three patients with prior uncertain KMT2B findings. The workflow detected characteristic deviations in the KMT2B episignature score in two cases with previously unresolved or missed variants, and refuted an ambiguous indel call in the third. Combining variant detection with DNA methylation analysis removes the need for sequential testing.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Getting the variant and the episignature from a single run is the real argument: today, resolving such a case means sequencing and then a methylation array, often in two laboratories months apart. Three patients, however, allow no estimate of sensitivity or specificity, and the result depends entirely on a validated episignature classifier already existing for the gene in question — true today for only a minority of genes. A credible proof of concept, to be confirmed in an adequate series.

Analysis by Dr Thibaut Benquey