MC4R and Hyperinsulinemia: We found that carriers of these variants displayed the classical features of MC4R deficiency, including severe early-onset obesity, accelerated linear growth, early hyperinsulinemia (Martinelli et al., 2011), and low systolic blood pressure (Greenfield et al., 2009; Table S2), demonstrating that disruption of these mechanisms is sufficient to reduce MC4R function to a level that is physiologically significant.