339例核型正常的颈项透明层增厚胎儿的染色体微阵列分析

Chromosomal microarray analysis of 339 fetuses with increased nuchal translucency and normal karyotype

目的探讨染色体微阵列分析(chromosomal microarray analysis, CMA)技术在颈项透明层增厚但染色体核型正常胎儿病因检测中的应用价值。方法对2015年3月至2017年12月在深圳市妇幼保健院产前诊断中心就诊的孕早期(孕11+1~13周+6)胎儿颈项透明层≥3.0 mm的单胎妊娠孕妇行羊膜腔穿刺,同时进行染色体G显带核型分析及CMA。回顾性纳入染色体G显带核型分析正常的339例胎儿,对CMA检出致病性拷贝数变异(copy number variations, CNVs)及临床意义不明确的CNVs(variants of uncertain significance, VUS)的胎儿,抽取其父母外周血进行CMA验证。随访妊娠结局及生后情况。总结CMA结果,采用描述性统计分析。结果339例中共检出致病性CNVs的胎儿15例(4.4%),所检出的CNVs片段大小为68 kb^12.636 Mb,包括4例微重复及11例微缺失。其中有8种(9例)已知的综合征,分别为Williams-Beuren综合征、18p部分缺失综合征、Wolf-Hirschhorn综合征、22q11重复综合征、16p11.2缺失综合征、17p13.3重复综合征、16p11.2重复综合征各1例及DiGeorge综合征/腭心面综合征2例。检出VUS 11例,其中5例变异来自表型正常的父母,考虑为良性CNVs;其余6例为真正的VUS,占1.8%(6/339)。15例检出致病性CNVs的胎儿,失访1例;4例活产,其中2例随访至2岁,出现生长发育迟缓。11例检出VUS的胎儿中,9例活产,均随访至1岁暂未发现异常。结论在颈项透明层增厚但染色体核型正常胎儿中,CMA可检出传统核型分析无法识别的染色体微缺失/微重复,在产前诊断及遗传咨询中具有重要价值。

Objective To explore the value of chromosome microarray analysis (CMA) in determining the genetic etiology of fetuses with increased nuchal translucency (NT) but normal karyotype. Methods Amniocentesis, karyotype analysis and CMA were performed to singleton pregnant women with increased fetal NT (≥3.0 mm) in early pregnancy (11+1-13+6 gestational weeks) at Shenzhen Maternity and Child Healthcare Hospital from March 2015 to December 2017. A total of 339 fetuses with normal G banding karyotype analysis were recruited retrospectively. Peripheral blood samples were collected for CMA in parents whose fetuses were detected with pathogenic copy number variations (CNVs) or variants of uncertain significance (VUS). Descriptive analysis was used for CMA results. Moreover, Pregnancy outcomes and postnatal conditions of fetuses with abnormal CNVs were followed up. Results Pathogenic CNVs, ranging from 68 kb to 12.636 Mb, were detected in 15 out of the 339 fetuses (4.4%) including four microduplications and 11 microdeletions. Among them, there were eight known microdeletion or microduplication syndromes (nine cases) including Williams-Beuren syndrome, 18p deletion syndrome,Wolf-Hirschhorn syndrome, 22q11 duplication syndrome, 16p11.2 deletion syndrome, 17p13.3 duplication syndrome, 16p11.2 duplication syndrome (one case respectively) and DiGeorge syndrome/velocardiofacial syndrome (two cases). Of the 11 fetuses with VUS, five cases originated from parents with normal phenotype and the identified VUS were benign and the rest six were de novo mutations[1.8%(6/339)]. Of the 15 fetuses with pathogenic CNVs, one was lost to follow-up, four were live born and two of which was found to be growth retardation at the age of two. Among the 11 fetuses with VUS, nine were live born and no abnormality was reported in any cases at one year old. Conclusions For fetus with increased NT and normal karyotype, CMA is able to identify chromosomal microdeletion/microduplication that are not recognized by conventional karyotyping analysis, and may play an important role in prenatal diagnosis and genetic counseling.