The Clinical Phenotype and Genetic Analysis of Monogenic Non Syndromic Obesity Caused by MC4R Gene Variation.

ABSTRACT Objective The objective of this study was to investigate the clinical features and genetic variation of a patient with monogenic nonsyndromic obesity caused by melanocortin 4 receptor (MC4R) gene variation. Additionally, this study aims to provide a reference for the diagnosis of the disease. Methods A monogenic non syndromic obese patient who was admitted to Dongying People's Hospital in December 2024 was enrolled in the study. The clinical data and peripheral blood samples of the patient were collected. Whole‐exome sequencing was utilized to identify gene variants. Subsequently, bioinformatic analysis was performed on the candidate variants detected in the patient. The pathogenicity of the variant was evaluated in accordance with the Standards and Guidelines for the Classification of Genetic Variants, which were formulated by the American College of Medical Genetics and Genomics (ACMG). A comprehensive database was meticulously curated to encompass all previously documented monogenic non syndromic cases. A retrospective analysis was then conducted to systematically summarize the phenotypic and pathogenic variation spectrum of the MC4R gene. A comprehensive review of the extant literature on cellular and molecular genetics was conducted, with the objective of elucidating the discrepancies between the mutation location of the MC4R gene and its clinical phenotype. Results The results of the patient's case reveal that the subject is a 10‐year‐2‐month‐old female who exhibits the clinical manifestations of severe obesity, hyperinsulinemia, and accelerated puberty development. Whole‐exome sequencing revealed a missense mutation c.185A > G (p.Asn62Ser) in the MC4R gene. According to the ACMG guidelines, the variant was designated as pathogenic (PM2_Supporting + PM3_Supporting + PS4_Supporting + PS3_Moderate + PP1_Strong + PP3_Supporting). A comprehensive literature search yielded a total of 64 children with obesity caused by MC4R mutation. Regardless of the location of the mutation, whether in the transmembrane region or the topological region, no statistically significant differences were observed in age (months), gender, BMI, BMISDS, acanthosis nigricans, hyperinsulin, hyperappetite, and underlying diseases between the two groups. Interaction analysis revealed a significant modification effect of underlying disease status on the association between mutation location and BMI (P for interaction = 0.002–0.069). Among children without underlying diseases, topological region mutations were associated with higher BMI (β = 8.52, 95% CI: −3.20–20.24), whereas among those with underlying diseases, the effect was reversed (β = −9.73, 95% CI: −21.42–1.96), indicating opposite directions of effect across subgroups. Conclusion The present study has demonstrated that MC4R gene missense variants are among the most prevalent genetic factors contributing to monogenic nonsyndromic obesity. For children with early‐onset severe obesity, accelerated puberty, and hyperinsulinemia, the consideration of monogenic nonsyndromic obesity is imperative, and genetic testing should be utilized to confirm the diagnosis expeditiously. In the context of pediatric obese patients with underlying diseases, the effect of different mutation positions on BMI varies. These findings also expand the spectrum of MC4R variants.