Our results reinforce the role of the leptin–melanocortin pathway in obesity and bring to light other genes that may carry highly penetrant obesogenic single allele variants, such as FTO, NEGR1 and PPARG. The availability of an evidence-based algorithm for diagnostic analysis of early-onset obesity would be of great clinical interest. This evidence concerns the gene NEGR1 and obesity due to melanocortin 4 receptor deficiency.