Rare variants in key genes, gene families, or chromosomal regions that affect the MC4R pathway, including LEP, LEPR, MC4R, MRAP2, NCOA1 (encodes steroid receptor coactivator 1), PCSK1, POMC, SH2B1, SEMA3A-G, SIM1, genes associated with Bardet-Biedl syndrome (BBS), and the 16p11.2 chromosomal region, can disrupt MC4R pathway signaling and are associated with hyperphagia and/or early-onset, severe obesity [2, 5, 7, 8, 35–37]. This evidence concerns the gene SH2B1 and Bardet-Biedl syndrome.