Both extreme polygenic score and pathogenic MC4R mutations demonstrate incomplete penetrance – not all carriers manifest severe obesity. This observation is consistent with recent large-scale gene sequencing studies across a broad range of complex diseases, including diabetes, cardiovascular disease, and breast cancer (Flannick et al., 2013; Khera et al., 2016; Manickam et al., 2018). Additional studies of large unascertained populations are needed to determine whether a larger effect size for pathogenic MC4R mutations is noted among children or young adults – as has been suggested in prior reports (Farooqi et al., 2003; Stutzmann et al., 2008) – and the extent to which a favorable polygenic background can explain the absence of obesity noted among many mutation carriers.
