Candidate gene studies led to the identification of very rare variants that cause monogenic forms of severe obesity mostly by impacting the function of proteins involved in the central leptin-melanocortin pathway (Doche et al., 2012, O’Rahilly and Farooqi, 2008, Saeed et al., 2018, van der Klaauw and Farooqi, 2015). The gene discussed is LEP; the disease is obesity due to melanocortin 4 receptor deficiency.