MC4R and obesity due to melanocortin 4 receptor deficiency: LoF MC4R variants were first identified in people with hyperphagia and severe early-onset obesity 20 years ago (Vaisse et al., 1998, Yeo et al., 1998), and subsequently, over 300 rare variants that reduce cAMP accumulation have been identified, mostly in obese people (Collet et al., 2017, Stutzmann et al., 2008) (https://www.mc4r.org.uk/).