胎儿游离DNA无创产前筛查假阴性病例分析
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摘要
目的对2例胎儿游离DNA无创产前筛查(NIPS)假阴性病例进行回顾分析,探讨NIPS在临床中的规范化应用。方法回顾分析孕妇1和孕妇2孕期相关检测,对新生儿1应用高通量测序法和单核苷酸多态性(SNP)芯片进行染色体拷贝数的变异检测,对新生儿2使用多重连接探针扩增技术(MLPA)进行Prader-Willi综合征/Angelman综合征(PWS/AS)相关基因检测。结果孕妇1因超声提示脉络丛囊肿选择NIPS-PLUS检测,NIPS-PLUS结果低风险。孕晚期超声提示脉络丛囊肿、透明隔腔增宽、后颅窝池临界值,未做产前诊断。新生儿1高通量测序结果为seg[hg19]del(1)(p36.33p36.23),存在8.02Mb缺失,单核苷酸多态性(SNP)结果为arrg[hg19]1p36.33p36.23(752566-8774451)×1,存在8.02Mb缺失,为1p36缺失综合征。孕妇2因高龄进行NIPS-PLUS检测,NIPS-PLUS结果低风险,孕晚期进行性羊水增多,未做产前诊断。新生儿2 MLPA结果为PWS/AS相关基因存在拷贝数减半及完全甲基化状态,为父源性杂合缺失的Prader-Willi综合征。结论 NIPS对染色体微缺失综合征检测的准确性有待进一步提高,针对超声软指标异常的孕妇要慎重选择NIPS。合理规范应用NIPS可以早期高效检出染色体非整倍体胎儿,避免严重致残、致畸、致死性出生缺陷发生。
【Objective】To explore the application of non-invasive prenatal screening(NIPS) in clinical standardization through analyzing two false negative cases.【Methods】Pregnancy-related tests of case 1 and case 2 were retrospectively analyzed, high throughput sequencing and SNP chip were used to detect chromosome copy number variations in newborn 1, PWS/AS related genes were detected using MLPA in newborn 2.【Results】Pregnant woman 1 chose NIPS-PLUS due to ultrasonographic indications for choroid plexus cyst, which had a low-risk result. Ultrasonography in the third trimester of pregnancy suggested choroid plexus cyst, widened clear septum and critical value of posterior fossa cistern, but no prenatal diagnosis was done. For newborn 1, the high-throughput sequencing showed seg[hg19]del(1)(p36.33 p36.23), with a 8.02 Mb deletion. The SNP showed arrg[hg19]1 p36.33 p36.23(752566-8774451)×1, with a 8.02 Mb deletion, which was diagnosed as 1 p36 deletion syndrome. Pregnant woman 2 chose NIPS-PLUS due to her advanced age, which had a low-risk result. Amniotic fluid was increased in advanced stage of pregnancy,but no prenatal diagnosis was done. For newborn 2, the MLPA results indicated that the copy number of PWS/AS related genes was halved and fully methylated, which was diagnosed as Prader-willi syndrome of parent-derived hybridization deficiency.【Conclusion】The accuracy of NIPS detection for chromosomal microdeletion syndrome needs to be further improved. For pregnant women with abnormal ultrasound soft index, NIPS should be carefully selected. To avoid serious disability, teratogenic and fatal birth defects, the reasonable and standard application of NIPS can effectively detect the fetus with chromosome aneuploidy at an early stage.
【Objective】To explore the application of non-invasive prenatal screening(NIPS) in clinical standardization through analyzing two false negative cases.【Methods】Pregnancy-related tests of case 1 and case 2 were retrospectively analyzed, high throughput sequencing and SNP chip were used to detect chromosome copy number variations in newborn 1, PWS/AS related genes were detected using MLPA in newborn 2.【Results】Pregnant woman 1 chose NIPS-PLUS due to ultrasonographic indications for choroid plexus cyst, which had a low-risk result. Ultrasonography in the third trimester of pregnancy suggested choroid plexus cyst, widened clear septum and critical value of posterior fossa cistern, but no prenatal diagnosis was done. For newborn 1, the high-throughput sequencing showed seg[hg19]del(1)(p36.33 p36.23), with a 8.02 Mb deletion. The SNP showed arrg[hg19]1 p36.33 p36.23(752566-8774451)×1, with a 8.02 Mb deletion, which was diagnosed as 1 p36 deletion syndrome. Pregnant woman 2 chose NIPS-PLUS due to her advanced age, which had a low-risk result. Amniotic fluid was increased in advanced stage of pregnancy,but no prenatal diagnosis was done. For newborn 2, the MLPA results indicated that the copy number of PWS/AS related genes was halved and fully methylated, which was diagnosed as Prader-willi syndrome of parent-derived hybridization deficiency.【Conclusion】The accuracy of NIPS detection for chromosomal microdeletion syndrome needs to be further improved. For pregnant women with abnormal ultrasound soft index, NIPS should be carefully selected. To avoid serious disability, teratogenic and fatal birth defects, the reasonable and standard application of NIPS can effectively detect the fetus with chromosome aneuploidy at an early stage.
引文
[1]Lo YMD,Corbetta N,Chamberlain PF,et al.Presence of fetal DNA in maternal plasma and serum[J].Lancet,1997,350(9076):485-487.
[2]Breman A,Pursley AN,Hixson P,et al.Prenatal chromosomal microarray analysis in a diagnostic laboratory;experience with>1000 cases and review of the literature[J].Prenat Diagn,2012,32(4):351-361.
[3]袁路,张富青,刘敏,等.母体外周血胎儿游离DNA检测在临床诊断中的应用[J].中国医学工程,2014,22(2):37+40.
[4]Gregg AR,Skotko BG,Benkendorf JL,et al.Noninvasive prenatal screening for fetal aneuploidy,2016 update:a position statement of the American College of Medical Genetics and Genomics[J].Genet Med,2016,18(10):1056-1065.
[5]Wilson RD.Committee Opinion Summary No.640:Cell-free DNA screening for fetal aneuploidy[J].Obstet Gynecol,2015,126(3):691-692.
[6]Norton ME,Jacobsson B,Swamy GK,et al.Cell-free DNAanalysis for noninvasive examination of trisomy[J].N Engl J Med,2015,372(17):1589-1597.
[7]Zhang H,Gao Y,Jiang F,et al.Non-invasive prenatal testing for trisomies 21,18 and 13:clinical experience from 146,958 pregnancies[J].Ultrasound Obstet Gynecol,2015,45(5):530-538.
[8]Li R,Wan J,Zhang Y,et al.Detection of fetal copy number variants by non-invasive prenatal testing for common aneuploidies[J].Ultrasound Obstet Gynecol,2016,47(1):53-57.
[9]Lau TK,Cheung SW,Lo PS,et al.Non-invasive prenatal testing for fetal chromosomal abnormalities by low-coverage wholegenome sequencing of maternal plasma DNA:review of 1982consecutive cases in a single center[J].Ultrasound Obstet Gynecol,2014,43(3):254-264.
[10]Cheung SW,Patel A,Leung TY.Accutate description of DNA-based noninvasive prenatal screening[J].N Engl J Med,2015,372(17):1675-1677.
[11]文萍,薛莹,张芹,等.无创产前检测胎儿染色体非整倍体假阴性两例[J].中华医学遗传学杂志,2017,34(6):884-887.
[12]Van Opstal D,van Maarle MC,Lichtenbelt K,et al.Origin and clinical relevance of chromosomal aberrations other than the common trisomies detected by genome-wide NIPS:results of the TRIDENT study[J].Genet Med,2018,20(5):480-485.
[2]Breman A,Pursley AN,Hixson P,et al.Prenatal chromosomal microarray analysis in a diagnostic laboratory;experience with>1000 cases and review of the literature[J].Prenat Diagn,2012,32(4):351-361.
[3]袁路,张富青,刘敏,等.母体外周血胎儿游离DNA检测在临床诊断中的应用[J].中国医学工程,2014,22(2):37+40.
[4]Gregg AR,Skotko BG,Benkendorf JL,et al.Noninvasive prenatal screening for fetal aneuploidy,2016 update:a position statement of the American College of Medical Genetics and Genomics[J].Genet Med,2016,18(10):1056-1065.
[5]Wilson RD.Committee Opinion Summary No.640:Cell-free DNA screening for fetal aneuploidy[J].Obstet Gynecol,2015,126(3):691-692.
[6]Norton ME,Jacobsson B,Swamy GK,et al.Cell-free DNAanalysis for noninvasive examination of trisomy[J].N Engl J Med,2015,372(17):1589-1597.
[7]Zhang H,Gao Y,Jiang F,et al.Non-invasive prenatal testing for trisomies 21,18 and 13:clinical experience from 146,958 pregnancies[J].Ultrasound Obstet Gynecol,2015,45(5):530-538.
[8]Li R,Wan J,Zhang Y,et al.Detection of fetal copy number variants by non-invasive prenatal testing for common aneuploidies[J].Ultrasound Obstet Gynecol,2016,47(1):53-57.
[9]Lau TK,Cheung SW,Lo PS,et al.Non-invasive prenatal testing for fetal chromosomal abnormalities by low-coverage wholegenome sequencing of maternal plasma DNA:review of 1982consecutive cases in a single center[J].Ultrasound Obstet Gynecol,2014,43(3):254-264.
[10]Cheung SW,Patel A,Leung TY.Accutate description of DNA-based noninvasive prenatal screening[J].N Engl J Med,2015,372(17):1675-1677.
[11]文萍,薛莹,张芹,等.无创产前检测胎儿染色体非整倍体假阴性两例[J].中华医学遗传学杂志,2017,34(6):884-887.
[12]Van Opstal D,van Maarle MC,Lichtenbelt K,et al.Origin and clinical relevance of chromosomal aberrations other than the common trisomies detected by genome-wide NIPS:results of the TRIDENT study[J].Genet Med,2018,20(5):480-485.