At a population level, up to 70% of an individual’s body weight is thought to be genetically determined, with environmental, epigenetic, social and cultural factors determining phenotypic expression.16 Beyond genome-derived risk alleles, however, a number of genetic causes of severe early-onset obesity have been identified, accounting for 2% to 5% of severe obesity cases, due to mutations along the hypothalamic POMC/MC4R pathway, which will be discussed in more details in following sections.17 Here, MC4R is linked to obesity due to melanocortin 4 receptor deficiency.