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 has been reported to silence genes within the PWS cluster, and as such is a promising target to address the underlying genetic cause for the syndromes. Our published data shows that Smchd1-null embryos display loss of imprinting at Ndn and Magel2 within the PWS cluster. Furthermore, we were able to derive neural stem and progenitor cells from the hypothalamus, the key disease-relevant tissue. Smchd1 deletion in these cells also resulted in a loss of imprinting at the PWS cluster. In order for SMCHD1 to be a successful therapeutic target, it is important to investigate the effects of deleting SMCHD1 later in development on the imprinting status of the PWS cluster genes. This project will use a paternal null mouse model to address whether inducible deletion of Smchd1 in-vivo can cause loss of imprinting of critical PWS cluster genes and amelioration of disease phenotypes. Additionally, we plan to use SYS and PWS patient-derived hiPSCs to create hypothalamic-like neurons and test the effect of SMCHD1 deletion on the imprinting status of PWS cluster genes in disease cell lines in-vitro.