Imangaliyeva Altynay, Sikhayeva Nurgul, Bolatov Aidos, Utupov Talgat, Romanova Aliya, Akhmetollayev Ilyas, Zholdybayeva Elena
School of Medicine, Astana Medical University, Astana 010000, Kazakhstan.
"National Center for Biotechnology" LLP, JSC National Holding "Qazbiopharm", Korgalzhyn 13/1, Astana 010000, Kazakhstan.
Genes (Basel). 2025 Apr 28;16(5):508. doi: 10.3390/genes16050508.
: Severe early-onset obesity is a complex condition shaped by genetic and metabolic influences. The melanocortin 4 receptor () 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 variant to the observed phenotype. 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. Clinical assessment revealed a body mass index (BMI) of 44.68 kg/m, 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 :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. : Early genetic testing in individuals with severe obesity is essential for guiding personalized treatment strategies. Although the :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.
重度早发性肥胖是一种受遗传和代谢影响的复杂病症。黑皮质素4受体（MC4R）基因在能量平衡中起关键作用，致病变体与单基因形式的肥胖症相关。本研究旨在检查一名重度早发性肥胖患者及其家族的临床、代谢和遗传特征，以评估一个MC4R变体对所观察到的表型的贡献。一名22岁男性，3岁时首次被诊断为重度肥胖，接受了详细的临床、代谢和遗传评估。实验室评估包括胰岛素、血脂谱、尿酸和IGF-1水平。对该患者及其选定的家庭成员进行了全外显子组测序（WES），以确定与肥胖相关的潜在致病变体。临床评估显示体重指数（BMI）为44.68kg/m，高胰岛素血症（98.2µIU/mL），糖尿病前期（糖化血红蛋白：5.85%），血脂异常，高尿酸血症（421.0µmol/L），以及IGF-1水平升高（646.7ng/mL）。WES在该患者、其母亲和母系亲属中鉴定出一个杂合的MC4R:c.216C>G（p.Asn72Lys）变体。该变体在人群中的频率为0.0004%，SIFT、MutationTaster和PrimateAI预测其可能致病。然而，其分离模式提示一种复杂的遗传机制，而非经典常染色体显性或隐性遗传。结论：对重度肥胖个体进行早期基因检测对于指导个性化治疗策略至关重要。虽然MC4R:c.216C>G变体可能导致患者的代谢特征，但需要进一步的功能研究来确认其致病性，并阐明其在肥胖发病机制中的作用。
