Comparison of methylation episignatures in KMT2B - and KMT2D -related human disorders.

Aim & methods: To investigate peripheral blood methylation episignatures in KMT2B -related dystonia (DYT- KMT2B ), the authors undertook genome-wide methylation profiling of ∼2 M CpGs using a next-generation sequencing-based assay and compared the findings with those in controls and patients with KMT2D -related Kabuki syndrome type 1 (KS1). Results: A total of 1812 significantly differentially methylated CpG positions (false discovery rate < 0.05) were detected in DYT -KMT2B samples compared with controls. Multi-dimensional scaling analysis showed that the 10 DYT- KMT2B samples clustered together and separately from 29 controls and 10 with pathogenic variants in KMT2D . The authors found that most differentially methylated CpG positions were specific to one disorder and that all (DYT- KMT2B ) and most (Kabuki syndrome type 1) methylation alterations in CpG islands were gain of methylation events. Conclusion: Using sensitive methylation profiling methodology, the authors replicated recent reports of a methylation episignature for DYT- KMT2B. These findings will facilitate the development of episignature-based assays to improve diagnostic accuracy.