全外显子家系测序在WDR35基因复合杂合变异导致SRPS-5胎儿产前诊断中的价值

Role of the prenatal diagnosis of SRPS-5 neonate caused by compound heterozygous mutation of WDR35 by Trio-WES

目的探讨全外显子家系测序(Trio-WES)在诊断WDR35基因复合杂合变异导致短肋-多指综合征5型(SRPS-5)中的应用价值。方法收集1例引产儿产前诊断的临床资料,采用Trio-WES对引产儿皮肤组织及其父母外周血进行基因测序,采用SIFT、PolyPhen-2及Mutation Taster软件对筛选出的可疑变异进行生物危害性分析,并建立模型预测变异可能导致的蛋白结构变化。结果引产儿母亲孕22^(+3)周时的超声检查结果提示胎儿四肢长骨发育水平明显滞后,伴双侧肱骨、股骨弯曲,胸围小且胸腔狭窄,肋骨短且双肺受压变小。基因测序提示胎儿WDR35基因存在复合杂合变异,分别为父亲携带的c.799G>A/p.Val267Met杂合变异与母亲携带的chr2:20151176-20151245杂合缺失变异。检索Pubmed和HGMD数据库均未发现该变异相关报道,属WDR35基因的新变异,其中变异位点c.799G>A/p.Val267Met在多物种间高度保守,蛋白结构预测提示可能改变局部空间稳定性。结论WDR35基因缺陷可能是患儿长骨明显短且弯曲,短肋伴肺发育不良等症状的致病因素。Trio-WES可精确诊断胎儿期SRPS-5。

Objective To investigate the role of prenatal diagnosis of a neonate of short-rib polydactyly syndrome-5(SRPS-5)induced by a compound heterozygous mutation of WDR35 by trio-whole exome sequencing(trio-WES).Methods The clinical data of prenatal diagnosis of a neonate were collected.The genes of induced labor tissues and parents were determined by trio-WES.The biohazard analysis of the suspicious variant was carried out by using SIFT,PolyPhen-2 and Mutation Taster software,and the model was established to predict the protein structure changes caused by the mutation.Results At 22^(+3) weeks of gestation,ultrasound examination showed that fetal limb long bone had developmental delay,with bilateral humerus and femur bending,narrow chest cavity and reduced chest circumference,shortened ribs and compressed lungs.The gene test showed that there were compound heterozygous mutations in WDR35 in fetus,which were heterozygous mutation in father(c.799G>A/p.Val267Met)and loss of heterozygous mutation in chr2:20151176-2015124 in mother.The 2 mutations searched from PubMed and HGMD databases had not been reported.There were new mutations of WDR35.The c.799G>A/p.Val267Met was highly conserved among species,and the prediction of protein structure suggested that it might change the local spatial stability.Conclusions The defect of WDR35 may be the pathogenic factor of the fetal long bone shortening with bending,short rib with lung dysplasia and other symptoms,and the accurate diagnosis of SRPS-5 can be made by trio-WES.