外显子目标区域捕获技术在胎儿骨骼畸形产前诊断中的应用——附30例临床病例分析  

Application of Targeted Exon Capture in Prenatal Diagnosis of Fetal Skeletal Dysplasia——with Analysis of 30 Clinical Cases

作　　者：刘妍[1] 吴青青[2] 杨怡珂[1] 梁颖[3] 张铁娟[2] 梁娜[2] 杨丽曼[2] LIU Yan;WU Qingqing;YANG Yike;LIANG Ying;ZHANG Tiejuan;LIANG Na;YANG Liman(Department of Obstetrics;Department of Ultrasound;Department of Radiology,Beijing Obstetrics and Gynecology Hospital,Capital Medical University,Beijing 100026,China)

机构地区：[1]首都医科大学附属北京妇产医院产科,北京100026 [2]首都医科大学附属北京妇产医院超声科,北京100026 [3]首都医科大学附属北京妇产医院放射科,北京100026

出　　处：《医学综述》2018年第16期3279-3288,共10页Medical Recapitulate

基　　金：北京市医院管理局"登峰"人才培养计划(DFL20151302);首都医科大学基础-临床科研合作基金(14JL08)

摘　　要：目的探讨胎儿骨骼发育异常的基因诊断,为胎儿骨骼畸形的产前诊断分析及遗传咨询指导提供相应理论依据。方法选择2014年1月至2017年6月在首都医科大学附属北京妇产医院超声提示胎儿骨骼发育异常的30例病例为研究对象,其中15例胎儿局部骨骼畸形,15例胎儿短肢畸形。所有病例均留取胎儿脐血、羊水或流产组织,按技术路线依次进行胎儿染色体、全基因组测序及363个骨骼相关致病基因全外显子检测,并同时留取父母血样进行Sanger验证。结果 30例骨骼发育不良病例中,2例18-三体,余28例染色体正常的胎儿均未发现与骨骼发育异常相关的微缺失/微重复变异,21例均携带骨病相关基因。6例短肢畸形患者检测出胶原类基因突变,7例检测出携带成纤维细胞生长因子受体3基因的杂合已知致病突变,其余分别携带TP63、EBP、CHRNG、FLNB、SOX9等基因。其中3例复合杂合突变(CHRNG、COL11A2、SOX9)分别来源于表型健康的夫妻双方。结论目标区域外显子捕获技术能显著提高胎儿骨骼发育异常的产前诊断阳性率,为患者提供更全面的产前诊断分析、遗传咨询指导、手术及药物靶向治疗。Objective To explore genetic diagnosis of fetal skeletal dysplasia in order to provide a theoretical basis for prenatal diagnosis and genetic counseling for fetal skeletal malformations. Methods A total of 30 cases diagnosed as fetal skeletal malformations by ultrasound in Beijing Obstetrics and Gynecology Hospital,Capital Medical University from Jan.2014 to Jun. 2017 were enrolled,including 15 cases diagnosed with local skeletal malformations,and 15 cases with short limb deformity. Fetal umbilical cord blood,amniotic fluid,or fetal tissues were collected. Fetal chromosomal analysis,whole genome sequencing and 363 skeletal abnormality-related gene exon tests were conducted; blood samples were collected from the parents and underwent Sanger sequencing validation. Results Among the 30 cases,two cases were diagnosed 18-trisomy,and pathologic microdeletion or microduplication associated with skeletal dysplasia were not detected in the remaining28 cases with normal chromosomes. Known pathogenic mutations were detected in 21 cases,six cases were detected with collagen genes mutations and seven cases were detected with mutations of fibroblast growth factor receptor 3,and the rest carried TP63,EBP,CHRNG,FLNB,SOX9 and other genes. Three patients carried compound heterozygous mutations（ CHRNG,COL11 A2,SOX9）,which respectively derived from the father and mother with a healthy phenotype. Conclusion Targeted sequencing capture techniques can significantly improve the positive prenatal diagnosis rate of fetal skeletal dysplasia,providing more comprehensive prenatal diagnostic analysis and genetic counseling for early identification and possible intervention.

关 键 词：胎儿骨骼发育异常 染色体 全基因组测序 全外显子检测 产前诊断 遗传咨询 

分 类 号：R715.5[医药卫生—妇产科学]