3例SHOX基因杂合性缺失致Leri-Weill软骨生成障碍胎儿的遗传学分析

Genetic analysis of Leri-Weill dyschondrosteosis caused by loss of heterozygosity of SHOXgene in 3fetuses

目的对3例骨骼发育异常胎儿及其父母行比较基因组杂交微阵列(array comparative genomic hybridization,aCGH)分析,探讨遗传学病因。方法超声检出胎儿骨骼发育异常孕妇3例(均为单胎妊娠),于超声引导下行羊膜腔穿刺术抽取羊水或行脐静脉穿刺术采集脐带血标本,同时采集3例孕妇及配偶外周血标本,进行染色体核型分析和aCGH检测。结果3例孕妇、孕妇配偶及胎儿G显带核型分析结果均未见异常。例1胎儿aCGH结果显示X染色体p22.33区域存在1.39Mb杂合性缺失(chrX:219609-1608358,hg19),胎儿父亲aCGH结果正常,家系验证结果表明胎儿杂合性缺失遗传自母亲。例2胎儿aCGH结果显示X染色体p22.33区域或Y染色体p11.32区域存在0.65Mb杂合性缺失(chrX:464439-1118325或chrY:414439-1068325,hg19),胎儿父母aCGH结果均正常,家系验证结果表明胎儿杂合性缺失为新发突变。例3胎儿aCGH结果显示Xp22.33区域存在0.19Mb杂合性缺失(chrX:550458-735001,hg19),胎儿父母aCGH结果正常,家系验证结果表明胎儿杂合性缺失为新发突变。3例胎儿缺失片段大小不等,均包含与胎儿表型相关的SHOX基因。例1胎儿出生后随访至20月龄,身高77.6cm,前囟门未闭合,无其他异常;例2、例3孕妇选择终止妊娠。结论SHOX基因杂合性缺失导致的Leri-Weill软骨生成障碍是3例胎儿骨骼发育异常的遗传学病因。

Objective To perform the array comparative genomic hybridization(aCGH)on 3fetuses with abnormal skeletal development,and to investigate the genetic causes.Methods Three pregnant women with fetal skeletal dysplasia detected by prenatal ultrasound received amniocentesis or cordocentesis under the guidance of ultrasound to collect amniotic fluid or umbilical cord blood.At the same time,the peripheral blood samples of 3pregnant women and their husbands were collected for chromosome karyotype analysis and aCGH detection.Results No abnormal karyotypes were found in 3fetuses and their parents.The fetal aCGH result of patient 1identified a 1.39Mb loss of heterozygosity in Xp22.33region(chrX:219609-1608358,hg19),and the aCGH result of the father was normal.The result of pedigree verification showed that the loss of heterozygosity was inherited from the mother.The fetal aCGH result of patient 2 identified a 0.65 Mb loss of heterozygosity in Xp22.33or Yp11.32region(chrX:464439-1118325 or chrY:414439-1068325,hg19),and the aCGH results of the parents were normal,which indicated that the deletion of the fetus was de novo.The fetal aCGH result of patient 3identified a 0.19Mb loss of heterozygosity in Xp22.33region(chrX:550458-735001,hg19),and the parents'aCGH results were normal,which demonstrated that the deletion of the fetus was de novo.The deletion fragments of 3fetuses were different in size but all contained SHOX gene which was related with fetal phenotype.The fetus of patient 1was followed up to 20months of age,with a height of 77.6cm and unclosed anterior fontanel.The patients 2and 3chose to terminate pregnancy.Conclusion Leri-Weill dyschondrogenesis caused by loss of heterozygosity of SHOXgene is the genetic cause of skeletal dysplasia in these three fetuses.