NIPBL基因剪接变异致德朗热综合征1型胎儿的产前诊断及遗传学分析  

Prenatal diagnosis and genetic analysis of a fetus with Cornelia de Lange syndrome type 1 due to a splicing variant of NIPBL gene

作　　者：梁磊[1] 王海欣 蔡泽宇 赵建荣[1] Liang Lei;Wang Haixin;Cai Zeyu;Zhao Jianrong(Prenatal Diagnosis Center,the Affiliated Hospital of Inner Mongolia Medical University,Hohhot,Nei Monggol 010050,China;Department of Nephrology,the Affiliated Hospital of Inner Mongolia Medical Universy,Hohhot,Nei Monggol 010050,China)

机构地区：[1]内蒙古医科大学附属医院产前诊断中心,呼和浩特010050 [2]内蒙古医科大学附属医院肾脏内科,呼和浩特010050

出　　处：《中华医学遗传学杂志》2022年第10期1107-1110,共4页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金(81960130)。

摘　　要：目的分析一例德朗热综合征1型胎儿的遗传学病因。方法收集胎儿及其父母的临床资料,采集羊水及父母的外周血样,提取基因组DNA,通过全基因组低深度重测序、全外显子组测序(whole exome sequencing,WES)及Sanger测序筛查NIPBL基因的变异位点,参考美国医学遗传学与基因组学学会指南判断变异的致病性,利用minigene技术分析变异对mRNA的影响。结果测序结果提示胎儿NIPBL基因的内含子上存在c.5808+5G>A杂合变异,预测可能影响mRNA剪接,胎儿父母未检测到相同的变异。上述变异在ExAC、1000G、dbSNP等数据库中均未见收录,综合分析判断其为有害变异。minigene实验结果证实该变异会影响mRNA剪接,导致第31外显子的跳跃。结论确诊了一例德朗热综合征1型胎儿。minigene实验可以在体外验证WES检测所发现的剪接变异,可为判断这类变异的致病性提供更多的证据。Objective To explore the genetic etiology of a fetus with Cornelia de Lange syndrome type 1.Methods Clinical data of the fetus was collected.Genomic DNA was extracted from amniotic fluid and peripheral blood samples of the parents and subjected to low-depth copy number variant sequencing,whole exome sequencing(WES)and Sanger sequencing.Pathogenicity of the candidate variant was predicted based on the guidelines of American College of Medical Genetics and Genomics(ACMG).Minigene assay was used to assess the effect of the variant on mRNA splicing.Results WES revealed that the fetus has harbored a heterozygous c.5808+5gG>A variant in the intron of the NIPBL gene,which was predicted to affect the mRNA splicing.The same variant was not detected in either parent.The variant was not recorded in ExAC,1000G and dbSNP databases.Comprehensive analysis showed that the variant was deleterious and may result in skipping of exon 31 during mRNA splicing.Conclusion The fetus was diagnosed with Cornelia de Lange syndrome type 1.Splicing variant identified by WES may be verified by minigene assay in vitro,which can provide more evidence for the prediction of its pathogenicity.

关 键 词：德朗热综合征1型 NIPBL基因 全外显子组测序 MINIGENE 

分 类 号：R714.5[医药卫生—妇产科学]