CNV-seq结合染色体核型分析技术在产前诊断胎儿染色体异常中的价值观察

Value of CNV-seq combined with karyotype analysis in prenatal diagnosis of fetal chromosome abnormalities

摘要

目的 探讨基因组拷贝数变异测序(CNV-seq)结合染色体核型分析技术在产前诊断胎儿染色体异常中的价值。方法 回顾性选取2019年6月至2022年6月于绵阳市人民医院产前诊断科行羊膜腔穿刺术且拷贝数变异(CNV)提示异常的107例孕妇为研究对象,分别行CNV-seq检测和染色体核型分析。结果 在107例孕妇的羊水样本中,染色体核型分析检出58例(54.21%)胎儿核型异常,包括染色体数目异常36例(62.07%),染色体结构异常11例(18.97%),嵌合体11例(18.97%).CNV-seq检测对染色体核型分析中的58例核型异常者均成功确诊,变异类型包括54例(93.10%)致病性,4例(6.90%)临床意义不明;CNV-seq检出13例嵌合体病例,其中2例(低于10%)染色体核型分析未检出.在49例核型未见异常羊水样本中,CNV-seq检出致病性变异类型20例(40.82%)、临床意义不明23例(46.94%)、可能良性2例(4.08%)、可能致病性1例(2.04%)、良性变异3例(6.12%).染色体核型分析产前诊断胎儿染色体异常的阳性率均明显低于CNV-seq检测及二者联合检测的阳性率(χ²=115.654,P<0.05);三种检测方法产前诊断胎儿染色体数目异常、染色体结构异常和嵌合体的检出率比较差异均无统计学意义(P>0.05)。结论 在胎儿染色体异常的产前诊断中,CNV-seq可高效、特异地检出染色体核型分析技术无法检出的致病性基因组CNVs,可为产前遗传咨询提供更详细的参考信息.

Abstract

Objective To investigate the value of genome copy number variation sequencing (CNV-seq) combined with karyotype analysis technology in prenatal diagnosis of fetal chromosome abnormalities. Methods A retrospective study was conducted on 107 pregnant women who underwent amniocentesis and were indicated to have copy number variation (CNV) from June 2019 to June 2022 at the department of prenatal diagnosis, Mianyang People's Hospital. All participants underwent both CNV-seq testing and karyotype analysis. Results In the amniotic fluid samples of 107 pregnant women, karyotype analysis identified 58 cases (54.21%) of fetal karyotype abnormalities, including 36 cases (62.07%) of numerical abnormalities, 11 cases (18.97%) of structural abnormalities and 11 cases (18.97%) of mosaicism. CNV-seq testing successfully confirmed all 58 karyotype abnormalities identified by karyotype analysis. Among these, 54 cases (93.10%) were pathogenic, and 4 cases (6.90%) had unknown clinical significance. Additionally, CNV-seq detected 13 cases of mosaicism, including 2 cases (less than 10%) that were not detected by karyotype analysis. In the 49 amniotic fluid samples with normal karyotypes, CNV-seq identified 20 cases (40.82%) of pathogenic variants, 23 cases (46.94%) of variants of unknown clinical significance, 2 cases (4.08%) of likely benign variants, 1 case (2.04%) of likely pathogenic variants and 3 cases (6.12%) of benign variants. The positive rate of fetal chromosomal abnormalities using karyotype analysis was significantly lower than that of CNV-seq and the combined testing method (χ²=115.654, P<0.05). There were no statistically significant differences in the detection rates for chromosomal numerical abnormalities, structural abnormalities, and mosaicism among the three testing methods (P>0.05). Conclusion In the prenatal diagnosis of fetal chromosome abnormalities, CNV-seq can effectively and specifically detect pathogenic genomic CNVs that cannot be identified by karyotype analysis. This provides more detailed reference information for prenatal genetic counseling.

关键词

基因组拷贝数变异测序 / 染色体核型分析 / 染色体异常 / 产前诊断

Key words

genome copy number variation sequencing / karyotype analysis / chromosome abnormality / prenatal diagnosis

参考文献

[1] 冯淑娴, 张春贤, 岳小珍, 等. 甘肃地区478例胎儿引产因素及胎儿畸形分布特征分析[J]. 中国妇产科临床杂志, 2022, 23(2): 179-180.

[2] El-Attar L M, Bahashwan A A, Bakhsh A D, et al. The prevalence and patterns of chromosome abnormalities in newborns with major congenital anomalies: a retrospective study from Saudi Arabia[J]. Intractable Rare Dis Res, 2021, 10(2): 81-87.

[3] Masoudzadeh N, Teimourian S. Comparison of quantitative fluorescent polymerase chain reaction and karyotype analysis for prenatal screening of chromosomal aneuploidies in 270 amniotic fluid samples[J]. J Perinat Med, 2019, 47(6): 631-636.

[4] 陈艺升, 王菲菲, 陆娄恺奕, 等. 扩展性无创产前检测对高风险胎儿的应用分析[J]. 中华预防医学杂志, 2021, 55(12): 1491-1495.

[5] 赵炜, 梁思颖, 谢宁, 等. 染色体核型分析联合染色体微阵列分析在平衡易位/倒位携带者产前诊断中的应用价值[J]. 中华围产医学杂志, 2022, 25(1): 35-41.

[6] Ma N, Xi H, Chen J, et al. Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism[J]. BMC Med Genomics, 2021, 14(1): 56.

[7] McGowan-Jordan J, Simons A, Schmid M, et al. ISCN 2016: An International System for Human Cytogenomic Nomenclature (2016), 2016.

[8] Nomenclature ISCoHC, McGowan-Jordan J, Hastings R J, et al. ISCN 2020: An International System for Human Cytogenomic Nomenclature (2020): Karger, 2020.

[9] 中华医学会医学遗传学分会临床遗传学组, 中国医师协会医学遗传医师分会遗传病产前诊断专业委员会, 中华预防医学会出生缺陷预防与控制专业委员会遗传病防控学组. 低深度全基因组测序技术在产前诊断中的应用专家共识[J]. 中华医学遗传学杂志, 2019, 36(4): 293-296.

[10] Riggs E R, Andersen E F, Cherry A M, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)[J]. Genet Med, 2020, 22(2): 245-257.

[11] 李敏, 张庆娥, 董晶晶, 等. 染色体微阵列分析在产前诊断中的应用价值[J]. 中国妇幼健康研究, 2022, 33(5): 96-101.

[12] 饶慧华, 刘艳秋, 陆清, 等. 染色体核型分析联合染色体微阵列分析对于产前诊断的价值[J]. 中华医学遗传学杂志, 2020, 37(4): 392-396.

[13] 袁碧波, 李娜, 龙英霞, 等. 拷贝数变异测序技术在无创产前筛查高风险且超声表现正常胎儿产前诊断中的价值研究[J]. 中国实用妇科与产科杂志, 2022, 38(4): 447-450.

[14] 魏友华, 朱文娟, 张延霞, 等. 高通量基因测序检测染色体拷贝数变异与染色体核型分析在产前诊断中联合应用的价值[J]. 中华医学遗传学杂志, 2020, 37(10): 1191-1193.

[15] Tenorio J, Nevado J, González-Meneses A, et al. Further definition of the proximal 19p13.3 microdeletion/microduplication syndrome and implication of PIAS4 as the major contributor[J]. Clin Genet, 2020, 97(3): 467-476.

[16] Chen X, Zhou C. Reciprocal translocation and robertsonian translocation in relation to semen parameters: a retrospective study and systematic review[J]. Andrologia, 2022, 54(1): e14262.

[17] 罗小金, 魏凤香, 郭岩芸, 等. 低深度全基因组测序对于检测孕早期流产物染色体异常的价值[J]. 中华医学遗传学杂志, 2021, 38(12): 1268-1270.

[18] 黄桂芳. CNV-seq联合染色体核型分析在产前诊断中的应用研究[J]. 实用妇科内分泌电子杂志, 2021, 8(3): 14-16.