Comparison of Methylation Episignatures in <i>KMT2B</i> - and <i>KMT2D</i> -Related Human Disorders

Abstract

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