全基因组染色体微阵列分析及核型分析在颈项透明层增厚胎儿遗传学诊断中的价值*

Comparative study of whole-genome chromosomal microarray analysis and karyotype in fetuses with increased nuchal translucency*

摘要:

目的 探讨全基因组染色体微阵列分析（CMA）及核型分析在颈项透明层（NT）增厚胎儿中的临床检测效能和价值，分析NT增厚在染色体显微及亚显微水平上的遗传学发病原因。方法 选取2017年1月 1日—2018年9月30日在安徽省妇幼保健院产前诊断中心就诊的62例早孕期（11～13+6周）孕妇，经超声检查提示胎儿NT厚度≥2.5?mm，经羊水穿刺获取标本，再行标准的“核型分析+CMA”检查，确定遗传学诊断，结合临床资料分析检测结果。结果 ①核型分析的检出率为16.13%（10/62），其中唐氏综合征5例，18三体 综合征2例，1例嵌合体，另有2例结构畸变；CMA总检出率为24.19%（15/62），7例非整倍体与核型结果一致，8例为染色体微缺失/微重复。②按照NT值分组，核型分析和CMA在2.5?mm≤NT<3.5?mm、3.5?mm≤NT<4.5?mm、NT≥4.5?mm组中检出率分别为13.33%（4/30）/20.00%（6/30）、22.73%（5/22）/ 22.73%（5/22）、10.00%（1/10）/40.00%（4/10）。③受检样本中3例核型与CMA结果不符，1例核型为46，XN（28)/47，XN，+mar（14），CMA显示12p13.33p11.1区段发生2次重复，1例核型为46，XN，t（1∶16）（q41∶q23）pat，CMA正常，1例核型提示18号衍生染色体46，XN，der（18），CMA提示18p11.32p11.21区带存在14.9?Mb缺失，同时Yp11.31p11.2区域存在约8.2?Mb重复。在52例核型正常、NT增厚的胎儿中，CMA额外检出6例（11.54%）亚显微拷贝数变异（CNV），大小介于459?kb～2.03?Mb，涉及1q21.1q21.2、2q13、Xq28、11p15.4等区带。结论 胎儿NT增厚与染色体异常关系密切，且随NT值升高合并染色体病风险增大，CMA能检测传统核型分析无法识别的染色体微缺失/微重复，建议对NT增厚胎儿，应采用核型分析+CMA的标准遗传学诊断模式。

Abstract:

Objective To investigate the clinical value of whole-genome chromosomal microarray analysis (CMA) and chromosome karyotype analysis in the genetic diagnosis of fetuses with increased nuchal translucency (NT) and the genetic etiology for fetuses with increased NT in microscopic and submicroscopic chromosomal aberrations. Method Sixty-two fetuses with increased NT (≥ 2.5 mm) in the Prenatal Diagnosis Center of Anhui Women and Child Health Care Hospital were collected between 11 and 13+6 gestational weeks. Amniocentesis were performed to obtain fetal specimens for standard karyotype analysis and CMA detection. The results were analyzed combined with the clinical data. Results ① All 62 cases were successfully detected, among which 10 cases were abnormal chromosome karyotypes and the positive rate was 16.13% (10/62), including five cases of trisomy 21, two cases of trisomy 18, one cases of mosaic and two cases of structural anomalies. Meanwhile, 15 specimens were shown abnormal results by CMA with detection rate of 24.19% (15/62), seven cases of aneuploidy were consist with karyotype analysis and microduplication/microdeletion were identified in eight cases.② For the fetuses with 2.5 mm ≤ NT < 3.5 mm, 3.5 mm ≤ NT < 4.5 mm, NT ≥ 4.5?mm, the rates of chromosome abnormality detected by karyotyping and CMA were 13.33% (4/30) / 20.00% (6/30), 22.73% (5/22) / 22.73% (5/22), 10.00% (1/10) / 40.00% (4/10), respectively.③ Three cases with abnormal karyotypes were inconsistent with their CMA results, one of which exhibited abnormal karyotype with 46, xx, t (1 : 16) (q41 : q23) pat, but a normal CMA; the second displayed a mosaic karyotype with 46, XN (28)/47, XN, +mar (14), but twice duplications at 12p13.33p11.1 was identified by CMA; and the third one shown derivative chromosome with 46, XN, der (18), but a 14.9 Mb deletion at 18p11.32p11.21 and a 8.2 Mb microduplication at Yp11.31p11.2 were detected by CMA. Among 52 cases with increased NT but a normal karyotype, 6 (11.54%, 6/52) submicroscopic copy number variations (CNV) were identified by CMA, which were ranging from 459 kb to 2.03 Mb and involving 1q21.1q21.2, 2q13, Xq28, 11p15.4. Conclusion Increased NT is significantly correlated with chromosome abnormality and CMA can identify chromosomal microdeletion/microduplication unrecognizable by conventional karyotype analysis. Whole-genome chromosomal microarray analysis combined with karyotyping analysis should be used as a standard prenatal diagnostic model for fetuses with increased NT.