Our results align with findings reported for an increasing number of genes (KSR2 (ref. 28), MRAP2 (ref. 29) and SRC-1 (ref. 30)) where complete disruption in mice causes obesity but where the penetrance of heterozygous rare LOF variants in humans is more variable and likely to be modified by other genetic and environmental factors. Here, KSR2 is linked to obesity due to melanocortin 4 receptor deficiency.