早发性重度肥胖患儿1例的临床及遗传学分析

Clinical and genetic analysis of a child with early-onset severe obesity

目的探讨1例早发性重度肥胖患儿的临床特征与遗传学病因。方法选取2020年8月5日就诊于杭州市儿童医院内分泌科的1例早发性重度肥胖患儿为研究对象。收集患儿的临床资料,采集患儿及其父母的外周静脉血样,对患儿进行全外显子组测序(WES),用Sanger测序对候选变异进行家系验证,并对其进行生物信息学分析。结果患儿为女性,2岁9月龄,临床表现为重度肥胖、颈部与腋下皮肤有色素沉积。WES检测结果提示,患儿携带MC4R基因c.831T>A(p.Cys277*)和c.184A>G(p.Asn62Asp)复合杂合变异。经Sanger测序验证分别遗传自其父亲和母亲。生物信息学分析:(1)MC4R基因c.831T>A(p.Cys277*)变异已被ClinVar数据库收录;检索1000 Genomes、ExAC及gnomAD数据库,该变异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)相关指南,评级为致病性变异。(2)MC4R基因c.184A>G(p.Asn62Asp)变异在ClinVar、1000 Genomes、ExAC及gnomAD数据库中均未见收录;经SIFT与PolyPhen-2等在线软件分析,均预测为有害变异。根据ACMG相关指南评级为疑似致病性变异。结论MC4R基因c.831T>A(p.Cys277*)和c.184A>G(p.Asn62Asp)复合杂合变异可能是早发性重度肥胖患儿的遗传学病因。上述发现丰富了MC4R基因的变异谱,为该患儿的临床诊断与遗传咨询提供了依据。

Objective To explore the clinical phenotype and genetic etiology of a child with early-onset severe obesity.Methods 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.Results 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 0.0004 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.Conclusion 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.