Genetic Insights into Severe Obesity: A Case Study of MC4R Variant Identification and Clinical Implications

Abstract

Background/Objectives: Severe early-onset obesity is a complex condition shaped by genetic and metabolic influences. The melanocortin 4 receptor (MC4R) gene plays a crucial role in energy balance, and pathogenic variants are associated with monogenic forms of obesity. This study aims to examine the clinical, metabolic, and genetic characteristics of a patient with severe early-onset obesity and his family, to assess the contribution of an MC4R variant to the observed phenotype. Methods: A 22-year-old male with severe obesity, first recognized at age 3, underwent detailed clinical, metabolic, and genetic evaluations. Laboratory assessments included insulin, lipid profile, uric acid, and IGF-1 levels. Whole-exome sequencing (WES) was performed on the patient and selected family members to identify potential pathogenic variants associated with obesity. Results: Clinical assessment revealed a body mass index (BMI) of 44.68 kg/m2, hyperinsulinemia (98.2 µIU/mL), prediabetes (HbA1c: 5.85%), dyslipidemia, hyperuricemia (421.0 µmol/L), and elevated IGF-1 levels (646.7 ng/mL). WES identified a heterozygous MC4R:c.216C>G (p.Asn72Lys) variant present in the patient, his mother, and maternal relatives. This variant, with a population frequency of 0.0004%, is predicted as likely pathogenic by SIFT, MutationTaster, and PrimateAI. However, its segregation pattern suggests a complex inheritance mechanism rather than classical autosomal dominant or recessive inheritance. Conclusions: Early genetic testing in individuals with severe obesity is essential for guiding personalized treatment strategies. Although the MC4R:c.216C>G variant may contribute to the patient’s metabolic profile, further functional studies are required to confirm its pathogenicity and elucidate its role in obesity pathogenesis.

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