五个遗传性多发性骨软骨瘤家系的基因变异分析和产前诊断  

Genetic analysis of five pedigrees affected with multiple osteochondromas

作　　者：白莹[1] 焦智慧[1] 刘宁[1] 胡爽 赵凯慧 孔祥东[1] Bai Ying;Jiao Zhihui;Liu Ning;Hu Shuang;Zhao Kaihui;Kong Xiangdong(Center of Prenatal Diagnosis,the First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450052,China)

机构地区：[1]郑州大学第一附属医院妇产医学部遗传与产前诊断中心,450052

出　　处：《中华医学遗传学杂志》2020年第7期717-720,共4页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金青年科学基金项目(81501851);河南省医学科技攻关计划项目(201702003)。

摘　　要：目的对5个遗传性多发性骨软骨瘤(multiple osteochondromas,MO)家系进行EXT1和EXT2基因变异分析,明确其致病原因,为家系的遗传咨询和产前诊断提供依据。方法应用二代测序(next generation sequencing,NGS)对5个MO家系的先证者进行MO相关致病基因EXT1、EXT2外显子检测,发现可疑致病位点后,应用Sanger双向测序对家系成员和200名正常个体进行变异位点的验证分析,应用多重连接探针扩增技术(multiple ligation-dependent probe amplification,MLPA)检测对家系成员和20名正常个体进行基因缺失变异验证分析,确定致病变异后,对其中2个家系的高危胎儿进行孕中期产前诊断。结果5个MO家系均检出EXT基因变异,分别为EXT1基因第2~3外显子缺失、EXT1基因c.1468dupC(p.Leu490ProfsX31)、EXT1基因c.2084delC(p.Pro695LeufsX11)、EXT2基因c.187delT(p.Phe63SerfsX29)、EXT2基因c.1362T>G(p.Tyr454X),其中EXT1基因第2~3外显子缺失、EXT1基因c.2084delC(p.Pro695LeufsX11)、EXT2基因c.187delT(p.Phe63SerfsX29)为尚未报道的新变异,在家系正常成员和正常对照中均未发现该变异。产前诊断结果显示家系1胎儿携带EXT1基因第2~3外显子杂合缺失变异,家系5胎儿携带EXT2基因c.1362T>G(p.Tyr454X)杂合变异。结论EXT1、EXT2基因变异是5个MO家系的致病病因,致病基因的检出为家系的产前基因诊断提供了依据。Objective To detect variants of EXT1 and EXT2 genes among five pedigrees affected with multiple osteochondromas and provide prenatal diagnosis for the families based on the results.Methods The EXT1 and EXT2 genes of the probands were analyzed by targeted next generation sequencing(NGS).Suspected pathological variants were validated by Sanger sequencing in the probands,their family members and 200 unrelated healthy controls.Multiple ligation-dependent probe amplification(MLPA)was used to confirm the presence of gross deletions.Prenatal diagnosis was provided for 2 couples carrying pathogenic or likely pathogenic variants.Results Five variants were detected in the pedigrees,which included EXT1 exon 2-3 deletion,c.1468dupC(p.Leu490ProfsX31),c.2084delC(p.Pro695LeufsX11),and EXT2 c.187delT(p.Phe63SerfsX29)and c.1362T>G(p.Tyr454X).Among these,EXT1 exon 2-3 deletion,c.2084delC(p.Pro695LeufsX11)and EXT2 c.187delT(p.Phe63SerfsX29)were unreported previously.The three novel variants were not found among unaffected members of the pedigree and the 200 healthy controls.Upon prenatal diagnosis,the two fetuses were found to carry the same variants of the the probands.Conclusion Pathological variants of the EXT1 and EXT2 genes probably underlie the multiple osteochondromas among the 5 pedigrees.Prenatal diagnosis based on the results can effectively reduce the birth of further offspring affected with the disease.

关 键 词：遗传性多发性骨软骨瘤 EXT1基因 EXT2基因 二代测序 产前诊断 

分 类 号：R714.5[医药卫生—妇产科学] R440[医药卫生—临床医学]