SIM1 and obesity due to melanocortin 4 receptor deficiency: This logic lay behind the elucidation of the impact on obesity of defects in SIM1. The original identification of SIM1 as a possible obesity gene was as a result of its disruption due to a chromosomal rearrangement (a balanced translocation) in a single individual with profound obesity [24]; this was followed by the identification, by exon sequencing, of rare SIM1 variants that co-segregate with syndromic obesity and of common variants implicated in common obesity [25], [26].