Advancing epigenetic signatures as functional biomarkers in rare diseases

Alterations of the DNA methylation (DNAm) status of the genome underlie an increasing number of rare diseases. Recently, DNAm has also emerged as a highly informative biomarker for diagnosing rare disorders, which can be associated with distinctive genome-wide DNAm patterns (i.e., episignatures). Indeed, episignature testing has proven to represent an effective orthogonal omics technology, providing independent functional evidence to support or prioritize specific diagnostic hypotheses for hundreds of rare diseases, and reclassify variants of uncertain significance (VUS) emerging from genomic sequencing. Furthermore, the stability and plasticity inherent in DNAm make it a promising tool for personalized medicine, including patient stratification and therapeutic monitoring. This review outlines current technologies and analytical methodologies for genome-wide DNAm profiling and explores potential avenues of research, emphasizing artificial intelligence and multiomics integration to effectively manage patients with rare and complex phenotypes. We critically assess the current limitations and future directions of genome-wide DNAm profiling to expand the implementation of DNAm signatures as functional biomarkers, highlighting their importance as supplementary tools to genomic sequencing in clinical and research settings.