全外显子测序对三例Kallmann综合征遗传病因研究  

Study on genetic etiology of three cases of Kallmann syndrome using whole-exome sequencing

作　　者：杨幼波[1] 张勤[1] 莫朝晖[1] 谢艳红[1] 何红晖[1] 金萍[1] Yang Youbo;Zhang Qin;Mo Zhaohui;Xie Yanhong;He Honghui;Jin Ping(Department of Endocrinology,The Third Xiangya Hospital,Central South University,Changsha 410007,China)

机构地区：[1]中南大学湘雅三医院内分泌科,湖南长沙410007

出　　处：《中华内分泌代谢杂志》2021年第11期985-990,共6页Chinese Journal of Endocrinology and Metabolism

基　　金：国家自然科学基金(81670730,81100583);湖南省自然科学基金(2016JJ4103)。

摘　　要：目的Kallmann综合征(Kallmann syndrome,KS)是一种以先天性低促性腺激素性性腺功能减退和嗅觉缺失为特征的遗传病。目前已经报道20余个基因与KS相关。本研究对3例KS患者进行全外显子测序,以进一步明确其遗传病因。方法收集3例KS患者及家属外周血提取基因组DNA,采用全外显子组测序进行基因学检测序筛选出的致病基因,并进行Sanger测序和家系验证,并通过生物信息学软件对突变位点进行功能分析。结果先证者1为25岁男性,表现为低促性腺激素性性腺功能减退、头发早灰及感音性耳聋,基因检测在SOX10基因中检出杂合错义突变c.475C>T(p.R159W),具有KS表型的先证者1母亲、姐妹和表姐均检测到该错义突变,符合常染色体显性遗传。先证者2为15岁男性,表现为低促性腺激素性性腺功能减退及左肾缺如,基因检测发现该患者有ANOS1基因c.844delC(p.R282Vfs*28)杂合突变。其母为c.844delC杂合突变携带者,临床表型正常,符合X连锁隐性遗传。先证者3为21岁女性,表现为低促性腺激素性腺功能减退及嗅觉缺失,基因检测在FGF17基因中检出杂合错义突变c.149G>A(p.R50Q),该突变经SIFT和PolyPhen2生物信息学预测为致病性错义突变,在HGDM数据库未见报道,认为是新发突变。结论KS是一种临床和遗传异质性很强的疾病,本研究在3例KS患者中通过外显子测序分别发现了ANOS1 c.844delC,SOX10 c.475C>T及FGF17 c.149G>A突变,进一步拓展了KS的突变谱及表型谱。Objective Kallmann syndrome(KS)is a complex genetic disease characterized by congenital hypogonadotropic hypogonadism and anosmia.More than 20 genes have been reported to be associated with KS.Herein,we explore potential genetic aberration in 3 KS patients using the whole-exome sequencing.The potentially pathogenic variants filtered were validated by Sanger sequencing.Methods Genomic DNA was extracted from the peripheral blood of 3 patients with KS and their family members.Sanger sequencing and pedigree verification were performed on the pathogenic variants identified using whole-exome sequencing.The function of the mutation sites were analyzed with bioinformatics software.Results The proband 1 was a 25 years old male,characterized by lower gonadotropin gonad hypofunction,early grey hair and bilateral sensorineural hearing loss.A heterozygous mutation c.475C>T(p.R159W)of SOX10 gene was detected in the proband 1.His mother,sister and cousin who had KS phenotype were also found carrying this mutation,showing an autosomal dominant inheritance.The proband 2 was a 15-year-old male with hypogonadotropic hypogonadism and unilateral renal agenesis.The proband was hemizygous for c.844delC(p.R282Vfs*28)of ANOS1 gene,his mother was heterozygous for the mutation,which was consistent with the X-linked recessive inheritance.The proband 3 was a 21 years old female,characterized by hypogonadotropic hypogonadism and anosmia.A heterozygous missense mutation c.149G>A(p.R50Q)was detected in FGF17 gene.The mutation p.R50Q was predicted to be pathogenic by the SIFT and PolyPhen2 programs,and has not been reported in HGDM database yet,which considered to be a novel mutation.Conclusion KS is a clinically and genetically heterogeneous disease.In this study,ANOS1 c.844delC,SOX10 c.475C>T and FGF17 c.149G>A mutations were found in 3 patients with KS by whole exome sequencing,which would expand the genotypic and phenotype spectrum of KS.

关 键 词：KALLMANN综合征 ANOS1基因 SOX10基因 FGF17基因 突变 

分 类 号：R596[医药卫生—内科学]