Aykut Ayça, Özen Samim, Gökşen Damla, Ata Aysun, Onay Hüseyin, Atik Tahir, Darcan Şükran, Özkinay Ferda
Department of Medical Genetics, Ege University School of Medicine, İzmir, Turkey.
Department of Pediatric Endocrinology, Ege University School of Medicine, İzmir, Turkey.
Eur J Pediatr. 2020 Sep;179(9):1445-1452. doi: 10.1007/s00431-020-03630-7. Epub 2020 Mar 18.
Melanocortin 4 receptor gene plays an important role in food intake, energy balance, and weight control. The autosomal dominantly inherited MC4R variants cause obesity by causing hyperphagia and decreased sense of satiety. Homozygous variants are rarely reported, and they cause earlier/severe obesity. Our objective is to determine the MC4R gene variant frequency in children and adolescents with familial early-onset obesity. One hundred thirty-nine children and adolescents (57 girls/82 boys) whose weight increase started before the age of 5 years and who had early-onset obesity in at least one of their first-degree relatives were included in the study. Obesity is defined as body mass index (BMI) of ≥ 95th percentile, and as extreme obesity is defined if the BMI ≥ 120% of the 95th percentile or ≥ 35 kg/m. Children having genetic syndromes associated with obesity and mental retardation or taking drugs that promote changes in eating behavior or weight were excluded from the study. Coding region of the MC4R gene was sequenced by using the Illumina MiSeq Next Generation Sequencing System. The mean age of the patients was 7.3 ± 3.7 years, and the mean BMI SDS was 3.7 ± 0.7. While 118 patients (85%) were prepubertal, 21 patients (15%) were pubertal. Seven different variants were identified in 12 patients by giving a variant detection rate of 8.6%, of these five were previously identified missense variants p.N274S, p.S136F, p.V166I, p.R165W, and p.I291SfsX10. One homozygous variant p.I291SfsX10 (c.870delG) was detected in a severely obese 2-year-old boy, and other variants were heterozygous. Two novel variants were found: p.M200del and p.S188L. By using the in silico analysis software, these novel variants were predicted to be disease causing.Conclusion: MC4R gene variants are quite common in childhood obesity in Turkish population. Screening the variants in MC4R gene is necessary in patients with severe childhood-onset obesity. In such patients, comorbidities of obesity can be seen from early years. What is known • The frequency of MC4R mutations in obese patients was approximately 0-6.3%. What is new • In obese Turkish pediatric population, unlike other European countries, MC4R gene variants are quite common as we found a variant rate of 8.6% • We believe it is necessary to screen the variants in MC4R gene in patients with severe childhood-onset obesity and who had early-onset obesity in at least one of their first-degree relatives in Turkish population.
黑皮质素4受体基因在食物摄入、能量平衡和体重控制中起重要作用。常染色体显性遗传的MC4R变异通过导致食欲亢进和饱腹感降低而引起肥胖。纯合子变异很少被报道，它们会导致更早/更严重的肥胖。我们的目的是确定家族性早发性肥胖儿童和青少年中MC4R基因变异的频率。139名儿童和青少年（57名女孩/82名男孩）被纳入研究，他们在5岁前体重开始增加，且至少有一位一级亲属患有早发性肥胖。肥胖定义为体重指数（BMI）≥第95百分位数，极端肥胖定义为BMI≥第95百分位数的120%或≥35kg/m²。患有与肥胖和智力发育迟缓相关的遗传综合征或正在服用促进饮食行为或体重变化药物的儿童被排除在研究之外。使用Illumina MiSeq下一代测序系统对MC4R基因的编码区进行测序。患者的平均年龄为7.3±3.7岁，平均BMI标准差为3.7±0.7。118名患者（85%）为青春期前，21名患者（15%）为青春期。在12名患者中鉴定出7种不同的变异，变异检出率为8.6%，其中5种是先前鉴定出的错义变异p.N274S、p.S136F、p.V166I、p.R165W和p.I291SfsX10。在一名重度肥胖的2岁男孩中检测到一个纯合子变异p.I291SfsX10（c.870delG），其他变异为杂合子。发现了两种新变异：p.M200del和p.Sl88L。通过使用计算机分析软件，预测这些新变异会导致疾病。结论：在土耳其人群中，MC4R基因变异在儿童肥胖中相当常见。对重度儿童期起病肥胖患者进行MC4R基因变异筛查是必要的。在这类患者中，肥胖的合并症从早年就可见到。已知信息•肥胖患者中MC4R突变的频率约为0 - 6.3%。新发现•在肥胖的土耳其儿科人群中，与其他欧洲国家不同，MC4R基因变异相当常见，因为我们发现变异率为8.6%•我们认为，对土耳其人群中重度儿童期起病肥胖且至少有一位一级亲属患有早发性肥胖的患者进行MC4R基因变异筛查是必要的。
