A hallmark symptom of PWS is extreme, unrelenting hyperphagia associated with obesity. Other medical characteristics of individuals with PWS include low circulating growth hormone, short stature, adrenal insufficiency, hypothyroidism, and hypogonadism. Additionally, individuals with PWS have decreased levels of circulating fasting insulin compared to age and BMI matched controls and are also hyperghrelinemic. At a physiological level, we are endeavoring to locate a common mechanism for these characteristics. Individuals with microdeletions in the PWS locus also present with all major phenotypes of PWS, identifying a minimum critical deletion region (MCDR) that is sufficient to cause all major PWS phenotypes. The MCDR contains three paternally expressed genes all of which are non-coding: SNORD109A, SNORD116, and IPW. We are using patient-specific iPSC-derived neurons to model PWS in vitro working particularly on the molecular physiology of SNORD116. We are using the CRISPR/Cas9 system to create an allelic series that includes SNORD116, SNORD109A, and IPW on the same genetic background.