[Study of genetic etiology in fetuses with severely short limbs in the first and second trimester using whole exome sequencing].

Objective: To investigate pathogenic genes related to the phenotype of fetus with severely short limbs in the first and second trimester by whole exome sequencing (WES). Methods: Thirteen fetuses with severely short limbs detected by ultrasonography in the first and second trimester admitted in Chinese PLA General Hospital from September 2016 to June 2018 were collected. All cases were performed induced abortion, 6 of which were carried out karyotype analysis of amniotic fluid at the same time. WES and copy number variations (CNV) were performed on specimens from fetal tissues after labor induction. The suspected pathogenic mutations were validated by Sanger sequencing reactions. Results: No abnormal karyotypes or pathological CNV were found. In 10 fetuses, pathogenic or possibly pathogenic mutations were detected in the following genes: COL2A1, FGFR3, COL1A1, COL1A2, DYNC2LI1 and TRIP11, all of which were essential to skeletal development. The diagnostic yield of WES in the fetuses with severe short limbs was 10/13. Conclusions: In the first and second trimester, most of the fetuses with extremely short limbs suffer from monogenic diseases. WES is likely to be a valuable diagnostic testing option for the fetuses with severe short limbs.目的： 使用全外显子组测序（WES）为妊娠早、中期严重肢体短小胎儿查找致病原因。 方法： 收集2016年9月至2018年6月解放军总医院收治的妊娠早、中期严重肢体短小胎儿共13例。13例孕妇知情同意后均引产，其中6例同时取羊水行染色体核型分析；引产后取胎儿组织提取基因组DNA，行全基因组拷贝数变异（CNV）检测和WES，并对WES检测到的可疑致病位点行Sanger测序验证。 结果： 行染色体核型分析的6例胎儿染色体核型均未见异常；13例胎儿CNV检测均未见变异。13例胎儿的WES结果示，10例胎儿发现致病或可能致病的调控骨骼系统发育的关键基因突变，包括COL2A1、FGFR3、COL1A1、COL1A2、DYNC2LI1、TRIP11基因等；余3例未发现疾病相关性较高的基因变异。WES对妊娠早、中期严重肢体短小胎儿的诊断率为10/13。 结论： 妊娠早、中期胎儿严重肢体短小多为单基因遗传病，使用WES的诊断率高，可为大部分患儿查明致病原因。.