Clinical Institute of Special Laboratory Diagnostics, University Children's Hospital, University Medical Center Ljubljana (UMC), Ljubljana, Slovenia.
Department of Pediatrics Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, University Medical Center Ljubljana (UMC), Ljubljana, Slovenia.
Front Endocrinol (Lausanne). 2022 Apr 29;13:832911. doi: 10.3389/fendo.2022.832911. eCollection 2022.
Monogenic obesity is a severe, genetically determined disorder that affects up to 1/1000 newborns. Recent reports on potential new therapeutics and innovative clinical approaches have highlighted the need for early identification of individuals with rare genetic variants that can alter the functioning of the leptin-melanocortin signalling pathway, in order to speed up clinical intervention and reduce the risk of chronic complications. Therefore, next-generation DNA sequencing of central genes in the leptin-melanocortin pathway was performed in 1508 children and adolescents with and without obesity, aged 2-19 years. The recruited cohort comprised approximately 5% of the national paediatric population with obesity. The model-estimated effect size of rare variants in the leptin-melanocortin signalling pathway on longitudinal weight gain between carriers and non-carriers was derived. In total, 21 (1.4%) participants had known disease-causing heterozygous variants (DCVs) in the genes under investigation, and 62 (4.1%) participants were carriers of rare variants of unknown clinical significance (VUS). The estimated frequency of potential genetic variants associated with obesity (including rare VUS) ranged between 1/150 (VUS and DCV) and 1/850 (DCV) and differed significantly between participants with and without obesity. On average, the variants identified would result in approximately 7.6 kg (7.0-12.9 kg at the 95th percentile of body weight) (girls) and 8.4 kg (8.2-14.4 kg) (boys) of additional weight gain in carriers at age 18 years compared with subjects without obesity. In conclusion, children with a genetic predisposition to obesity can be promptly identified and may account for more than 6% of obesity cases. Early identification of genetic variants in the , , , and genes could reduce the societal burden and improve the clinical management of early severe childhood obesity and its implementation should be further investigated.
单基因肥胖症是一种严重的遗传性疾病，影响多达 1/1000 的新生儿。最近关于潜在新疗法和创新临床方法的报告强调了需要早期识别可能改变瘦素-黑素皮质素信号通路功能的罕见遗传变异个体的必要性，以便加速临床干预并降低慢性并发症的风险。因此，对 1508 名年龄在 2 至 19 岁的肥胖和非肥胖儿童和青少年进行了瘦素-黑素皮质素途径中核心基因的下一代 DNA 测序。所招募的队列大约占肥胖国家儿科人群的 5%。对携带者和非携带者之间瘦素-黑素皮质素信号通路中罕见变异的纵向体重增加的模型估计效应大小进行了推导。共有 21 名（1.4%）参与者在研究基因中具有已知的杂合致病变异（DCV），62 名（4.1%）参与者是罕见的临床意义不明变异（VUS）携带者。与肥胖相关的潜在遗传变异（包括罕见的 VUS）的估计频率在 1/150（VUS 和 DCV）和 1/850（DCV）之间，在肥胖和非肥胖参与者之间有显著差异。平均而言，在 18 岁时，与非肥胖者相比，携带这些变异的个体的体重将增加约 7.6 公斤（体重第 95 百分位数的 7.0-12.9 公斤）（女孩）和 8.4 公斤（8.2-14.4 公斤）（男孩）。总之，可以迅速识别出具有肥胖遗传倾向的儿童，这些儿童可能占肥胖病例的 6%以上。早期识别 、 、 、 和 基因中的遗传变异可以减轻社会负担并改善早期严重儿童肥胖的临床管理，应进一步研究其实施。
