DNA Methylation at a Single Locus of Human Genome Accurately Recapitulates Episignature of CREBBP-Related Rubinstein–Taybi Syndrome

The disruption of the epigenetic mechanisms of gene expression regulation due to the emergence of pathogenic variants in genes-encoding elements of epigenetic machinery leads to the development of chromatinopathies. This group of hereditary diseases includes 179 syndromes, some of which present with overlapping phenotypes. Despite the variety of approaches to molecular diagnostics of chromatinopathies, it is not always possible to establish the molecular diagnosis by traditional methods; thus, the issue of optimizing diagnostic algorithms remains relevant. One of the most rapidly expanding areas of post-genomic molecular diagnostics is episignature detection, which relies on genome-wide DNA methylation analysis. This article aims to represent an original approach to indirect diagnostics of chromatinopathies on the example of Rubinstein-Taybi syndrome 1, which is based on the analysis of the methylation level of a limited set of loci designed to reproduce its classic episignature. In the current study, we apply two methods of targeted quantitative analysis of DNA methylation, which are relatively accessible and can be integrated into diagnostic practice. We demonstrate that Rubinstein-Taybi syndrome 1 episignature may be successfully reduced to a single locus of human genome, and that quantitative bisulfite DNA methylation analysis at this locus allows accurate identification of the Rubinstein-Taybi syndrome 1 patients.