Abstract
DNA methylation is an essential epigenetic modification that plays a crucial role in regulating gene expression and maintaining genomic stability. With the advancement in sequencing technology, methylation studies have provided valuable insights into the diagnosis of rare diseases through the various identification of episignatures, epivariation, epioutliers, and allele-specific methylation. However, current methylation studies are not without limitations. This mini-review explores the current understanding of DNA methylation in rare diseases, highlighting the key mechanisms and diagnostic potential, and emphasizing the need for advanced methodologies and integrative approaches to enhance the understanding of disease progression and design more personable treatment for patients, given the nature of rare diseases.