Wang Pingping, Yang Suhong, Zhou Qiong, Zhang Jianmei, Zhang Yan, Li Dan
Department of Endocrinology, Hangzhou Children's Hospital, Hangzhou, Zhejiang 310014, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Apr 10;40(4):473-477. doi: 10.3760/cma.j.cn511374-20210411-00321.
To explore the clinical phenotype and genetic etiology of a child with early-onset severe obesity.
A child who presented at the Department of Endocrinology, Hangzhou Children's Hospital on August 5, 2020 was selected as the study subject. Clinical data of the child were reviewed. Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing (WES) was carried out on the child. Candidate variants were verified by Sanger sequencing and bioinformatic analysis.
This child was a 2-year-and-9-month girl featuring severe obesity with hyperpigmentation on the neck and armpit skin. WES revealed that she has harbored compound heterozygous variants of the MC4R gene, namely c.831T>A (p.Cys277*) and c.184A>G (p.Asn62Asp). Sanger sequencing confirmed that they were respectively inherited from her father and mother. The c.831T>A (p.Cys277*) has been recorded by the ClinVar database. Its carrier frequency among normal East Asians was 0.000 4 according to the 1000 Genomes, ExAC, and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was rated as pathogenic. The c.184A>G (p.Asn62Asp) has not been recorded in the ClinVar, 1000 Genomes, ExAC and gnomAD databases. Prediction using IFT and PolyPhen-2 online software suggested it to be deleterious. Based on the guidelines from the ACMG, it was determined as likely pathogenic.
The c.831T>A (p.Cys277*) and c.184A>G (p.Asn62Asp) compound heterozygous variants of the MC4R gene probably underlay the early-onset severe obesity in this child. Above finding has further expanded the spectrum of MC4R gene variants and provided a reference for the diagnosis and genetic counseling for this family.
探讨一名早发性重度肥胖儿童的临床表型及遗传病因。
选取2020年8月5日就诊于杭州市儿童医院内分泌科的一名儿童作为研究对象。回顾该儿童的临床资料。从该儿童及其父母的外周血样本中提取基因组DNA。对该儿童进行全外显子组测序（WES）。通过桑格测序和生物信息学分析验证候选变异。
该儿童为2岁9个月女童，患有重度肥胖症，颈部和腋窝皮肤有色素沉着。WES显示她携带MC4R基因的复合杂合变异，即c.831T>A（p.Cys277*）和c.184A>G（p.Asn62Asp）。桑格测序证实它们分别遗传自她的父亲和母亲。c.831T>A（p.Cys277*）已被ClinVar数据库收录。根据千人基因组、ExAC和gnomAD数据库，其在正常东亚人群中的携带频率为0.0004。根据美国医学遗传学与基因组学学会（ACMG）的指南，其被评为致病。c.184A>G（p.Asn62Asp）未被ClinVar、千人基因组、ExAC和gnomAD数据库收录。使用IFT和PolyPhen-2在线软件预测表明其有害。根据ACMG的指南，其被确定为可能致病。
MC4R基因的c.831T>A（p.Cys277*）和c.184A>G（p.Asn62Asp）复合杂合变异可能是该儿童早发性重度肥胖的病因。上述发现进一步扩展了MC4R基因变异谱，为该家庭的诊断和遗传咨询提供了参考。
