SIM1 and obesity due to melanocortin 4 receptor deficiency: To date, only a few of the described heterogeneous nonsynonymous loss-of function SIM1 variants fulfilled all of the criteria required for a monogenic obesity mutation (i.e. cosegregation with the obesity phenotype in the family, similar phenotype in all of the mutation carriers, and decreased transcriptional activity of the mutated SIM1 in in vitro studies) [7,8].