Aberrant DNA methylation patterns, including disturbances in genomic imprinting, have been linked to congenital imprinting disorders as well as various disease conditions, including cancer, chromatin disorders, and neurodevelopmental disorders. Some imprinting disorders, however, result in alterations in multiple imprinted regions (MLID) for which their exact causes are unknown. The aetiology of rare disorders, including MLID, remains largely uncertain, requiring further investigations to elucidate their underlying molecular mechanisms and their potential association with sporadic congenital anomalies. Due to these reasons, the clinical diagnosis can be challenging, and genetic testing is vital in order to confirm the diagnosis. Unfortunately, current diagnostic methods have significant limitations. To address these issues, I used novel epigenetic assays (ImprintSeq and EPIC-NGS) and genomic testing to investigate the molecular basis of human imprinting and chromatin disorders. A major aim was to provide a more accurate diagnosis of imprinting and chromatin disorders in order to improve the care of children with epigenetic disorders. ImprintSeq has demonstrated high accuracy, sensitivity, and specificity in the detection of methylation alterations at multiple imprinted regions, and EPIC-NGS has demonstrated the capability to detect disease methylation episignatures (e.g., childhood-onset dystonia, Kabuki syndrome, Sotos syndrome, and Luscan-Lumish syndrome). In particular, methylation episignature analysis enabled the identification of epigenotype-phenotype associations and provided insights into pathogenetic mechanisms of copy number variants (duplicates or deletions) and variants of uncertain significance (VUSs). In addition, genome-wide methylation profiling showed the potential to identify candidate genes involved in epigenetic disorders.

My PhD research has identified innovative diagnostic approaches for individuals afflicted by epigenetic disorders, highlighting their potential utility within clinical practice. Ultimately, my research aims to provide substantial benefits to individuals suffering from rare diseases by facilitating earlier and more precise diagnoses.