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

Imangaliyeva A. Sikhayeva N. Bolatov A. Utupov T. Romanova A. Akhmetollayev I. Zholdybayeva E.
May 2025 Multidisciplinary Digital Publishing Institute (MDPI)

Genes
2025 #16 Issue 5

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.

BMI heritability , Kazakh family , mutations , severe obesity , whole-exome sequencing

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School of Medicine, Astana Medical University, Astana, 010000, Kazakhstan
“National Center for Biotechnology” LLP, JSC National Holding “Qazbiopharm”, Korgalzhyn 13/1, Astana, 010000, Kazakhstan
Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, China

School of Medicine
“National Center for Biotechnology” LLP
Shenzhen University Medical School

10 лет помогаем публиковать статьи Международный издатель

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