Prader-Willi Syndrome (PWS) and Schaaf-Yang Syndrome (SYS) are neurodevelopmental disorders, with an estimated prevalence of 1:10,000. These syndromes arise due to genomic imprinting defects resulting in the lack of expression of a cluster of genes (the PWS cluster) or in the case of SYS one gene within the PWS cluster, MAGEL2. The epigenetic regulator Smchd1 is known to play a role in silencing PWS cluster genes on the maternal allele in mice. Removal of Smchd1 has been shown to result in activation of PWS genes from the silent maternally inherited allele without affecting Ube3a at risk of causing Angelman Syndrome. Using a reporter mouse model for Magel2 expression we have shown that in line with previous data, deletion of Smchd1 after its primary role in early development can result in reactivation of maternally inherited PWS genes in vivo in the brain. Furthermore, this reactivation is evident within the hypothalamus, the disease relevant area of the brain with no disruption to other Smchd1 targets, and the mice survive to adulthood. It follows now to move on to behavioural experiments in this model to test whether the level of reactivation is sufficient to affect disease phenotypes. Although much is known about Smchd1 function at the PWS cluster in mice, there is limited information about its role in humans. Using CRISPR-Cas9 technology we have created a system to knock out SMCHD1 in human cells. Through application of this system in patient-derived cell lines we have begun to investigate whether SMCHD1 also acts to silence maternally inherited PWS genes in humans. From this we aim to increase understanding of molecular mechanisms at work within the imprinted PWS cluster and to confirm viability of SMCHD1 as a target for epigenetic therapy of PWS and SYS.