全基因组拷贝数测序在颈项透明层增厚胎儿遗传学检查中的应用价值

Application of CNV-seq in the genetic detection of elevated fetal nuchal translucency

目的探讨全基因组拷贝数测序(CNV-seq)技术在颈项透明层(NT)增厚胎儿遗传学检查中的应用价值。方法选取早孕期超声筛查显示胎儿NT≥3.0 mm的孕妇110例,收集胎儿绒毛或羊水样本,进行染色体核型分析及CNV-seq检测,结合基因组拷贝数变异(CNV)国际数据库(ClinGen、ClinVar、DECIPHER、OMIM、UCSC)、正常人基因组变异数据库(DGV)及PubMed数据库等公共数据库中的数据,对检出的CNV的致病性进行分析。结果110例胎儿NT增厚的孕妇样本中,检出染色体核型异常26例(23.6%),其中25例为染色体非整倍体异常、1例为嵌合额外小标记染色体(sSMC)异常(嵌合比例为20%)。CNV-seq检出全部26例染色体数目异常及10例染色体微缺失/重复。CNV-seq检出的10例微缺失/重复样本中,有3例为可疑致病变异、7例为临床意义未明变异,明确定位染色体核型分析发现的1例胎儿携带的标记染色体来源于12 p13.33-p11.1(34.66 Mb,嵌合比例为20%)。结论CNV-seq可在检测染色体非整倍体的同时检测微小变异,并能界定标记染色体的来源及片段大小,有利于提高对NT增厚胎儿遗传病因的诊断效率。

Objective To investigate the application role of whole-genome copy number variation(CNV)sequencing(CNV-seq)in the genetic detection of elevated fetal nuchal translucency(NT).Methods The clinical data of 110 fetuses NT≥3.0 mm in the first trimester of pregnancy were collected and analyzed.The fetal villi or amniotic fluid samples with NT thickening were taken for karyotype analysis and CNV-seq.The pathogenicity of CNV was analyzed by querying the common database resources such as ClinGen,ClinVar,DECIPHER,OMIM,UCSC,the database of genomic variants(DGV)and PubMed.Results Among the 110 cases,26 cases were abnormal in karyotype,and the detection rate was 23.6%.Among them,25 cases were abnormal in aneuploidy,and 1 case was abnormal in small supernumerary marker chromosome(sSMC)(chimeric ratio was 20%).CNV-seq detected 36 abnormal cases and 10 cases of microdeletions/microduplications(7 cases of unknown clinical significance and 3 cases of suspected pathogenic variations)that could not be detected by karyotype analysis,and defined the origin of one sSMC derived from 12 p13.33-p11.1(34.66 Mb,chimeric ratio was 20%).Conclusions CNV-seq can detect the abnormal chromosome submicrostructure which is difficult to be finded by karyotype analysis,and it can define the source and fragment size of marker chromosome,which is helpful to improve the diagnosis of the genetic cause of the fetuses with NT thickening.