Applications and Challenges of Epigenetic Signature Detection in the Diagnostic Genomics Laboratory–Current and Future Directions

Background Epigenetic signature detection (ESD) identifies disease‐associated DNA methylation patterns and offers valuable insights beyond traditional genomic testing. Episignatures are increasingly recognised for their diagnostic potential, particularly in rare and complex disorders where conventional sequencing falls short. Main Body Several approaches are used for ESD, ranging from cost‐effective arrays to advanced sequencing methods. Methylation arrays and PCR remain accessible options, while whole‐genome and 5‐base sequencing offer greater resolution and integration with genomic data. Interpretation relies on robust reference datasets and bioinformatic tools, with machine learning aiding in classification accuracy. Clinically, ESD has proven valuable in diagnosing imprinting disorders, Mendelian epigenetic conditions and cancer subtypes—particularly central nervous system tumours. It also shows promise in variant classification and liquid biopsy applications. Emerging uses in pharmacogenomics and neuropsychiatric disorders are under investigation but require further validation. Despite its potential, implementation faces challenges including lack of standardisation, regulatory oversight and workforce training. Ethical concerns such as incidental findings, informed consent and data use must be carefully addressed. Conclusion ESD is a promising complement to genomic testing, with the potential to enhance diagnostic precision across a range of conditions. Continued technological advancement, validation and collaborative efforts will be essential for its successful and responsible clinical adoption.