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Recent genomic studies have identified a subclass of congenital intellectual disability disorders associated with overgrowth and obesity. These overgrowth and intellectual disability (OGID) syndromes are often caused by disruption of epigenetic regulatory genes, including the DNA methyltransferase DNMT3A and the histone methyltransferase NSD1. To date, however, the molecular mechanisms underlying the growth and obesity effects in OGID have not been investigated, and the risks for long-term metabolic dysfunction and the development of diabetes in these disorders remain undefined. Our work is focused on understanding how disruption of epigenetic pathways in OGID changes transcription in the nervous system and other tissues, ultimately leading to disease phenotypes. Our work has shown that two mouse models with unique heterozygous disruptions of the DNA methyltransferase DNMT3A show a progressive increase in bodyweight. Our ongoing work is investigating if this phenotype is observed across several novel mouse models of DNMT3A and NSD1 disruption in disease. Our goal of is to determine if these effects coincide with changes in body fat proportion, feeding behavior, or changes in activity. In related studies, we are investigating if manipulating the oxytocin pathway can alter feeding behaviors and reduce or reverse weight gain in DNMT3A mutant models. Access to EchoMRI imaging facilities through the DRC will allow us rigorously define body fat and body composition phenotypes in our mouse strains, providing key insights into the molecular underpinnings of obesity and overgrowth in OGIDs, and allowing for the assessment of diabetes and metabolic risks in these disorders. In the long term, this work can guide behavioral therapies or other interventions to improve overall health in individuals with OGID.