Context: Heterozygous mutations in the melanocortin-4 receptor (MC4R) gene are the most common monogenic form of severe obesity in children. There are conflicting reports regarding the prevalence, nature, and pathogenic effects of MC4R mutations in adults with severe late-onset obesity.

Objective: Our objective was to determine the prevalence of MC4R mutations in a cohort of severely obese adults and to determine the clinical phenotype and the phenotype-genotype relationship within adult MC4R mutation carriers.

Design and Setting: We conducted an observational study at a referral center.

Patients or Other Participants: Participants included 769 adult patients with body mass index of at least 35 kg/m² and 444 nonobese control individuals.

Interventions: There were no interventions.

Main Outcome Measures: We assessed the prevalence of pathogenic MC4R mutations, functional characteristics of the detected mutations, phenotype, and phenotype-genotype relationship within mutation carriers.

Results: The global prevalence of obesity-specific MC4R mutations was 2.6%, and the 95% confidence interval (CI₉₅) was 1.5–3.7. The prevalence of MC4R mutations was similar in patients developing obesity in childhood (2.83%; CI₉₅, 0.9–4.8) and in patients with a later onset of the disease (2.35%; CI₉₅, 0.9–3.8). Adult obese MC4R mutation carriers did not present with binge eating or with any specific clinical phenotype. The severity of the functional alterations of the mutated MC4Rs and in particular the intracellular retention of the receptor correlates both with the severity and the onset of the obesity in the mutation carriers.

Conclusions: Obese adult carriers of functionally relevant MC4R mutations do not specifically present with binge-eating disorder or a history of early-onset obesity. The onset and severity of the obesity in the carriers is related to the functional severity of the MC4R mutations.