We showed that carriers of rare disease-causing heterozygous variants (1.4% of participants) and VUS (4.1% of participants) in the leptin-melanocortin pathway are predisposed to early obesity (with a median SDS BMI of 3.3 and 2.7, respectively) and prone to 7.6 kg (7.0-12.9 kg at the 95th weight percentile) (girls) and 8.4 kg (8.2-14.4 kg) (boys) of additional weight gain compared to subjects without rare genetic variants in the leptin-melanocortin pathway. Here, LEP is linked to Obesity.