[Genetic diseases of epigenetic machinery]

The development of sequencing technologies and their increased accessibility in clinical services and genetic laboratories have considerably accelerated the identification of genetic variants associated with rare diseases (RDs). Among these, Mendelian disorders of the epigenetic machinery (MDEM) are rare monogenic diseases characterized by the presence of mutations in genes encoding epigenetic regulators that play a key role in organismal development and cellular functions. Loss of function of these regulators is expected to lead to epigenetic modifications that profoundly affect genome expression and cellular identity. Disruptions in DNA methylation profiles have been documented in MDEMs, emerging as a useful diagnostic tool. The current challenge is to determine whether and how these epigenomic alterations drive the mechanisms underlying the clinical manifestations in patients suffering from this class of diseases. Studying MDEMs may therefore shed light on the important role of epigenetic information in health and disease, particularly the mechanisms involved in the development and understanding of complex pathologies, such as neurodevelopmental disorders and cancer.