高通量測序技術(shù)在產(chǎn)前診斷中的臨床應(yīng)用
發(fā)布時(shí)間：2018-09-17 19:07
【摘要】：目的我國是出生缺陷高發(fā)國家之一,出生缺陷給患兒家庭及整個(gè)社會(huì)帶來沉重的經(jīng)濟(jì)負(fù)擔(dān)。如何進(jìn)行有效的產(chǎn)前診斷,降低出生缺陷,一直是產(chǎn)前診斷領(lǐng)域?qū)＜谊P(guān)注的熱點(diǎn)。產(chǎn)前診斷是預(yù)測胎兒出生前是否患有某種遺傳性疾病或先天畸形的方法,是在遺傳咨詢的基礎(chǔ)上,應(yīng)用現(xiàn)代生物學(xué)、生物化學(xué)、免疫遺傳學(xué)、細(xì)胞遺傳學(xué)、分子遺傳學(xué)等技術(shù),通過母體檢查或者對(duì)胚胎/胎兒直接檢測,診斷胎兒是否患有遺傳缺陷以及先天畸形。近年來,隨著孕婦優(yōu)生優(yōu)育意識(shí)的不斷加強(qiáng),我國產(chǎn)前診斷醫(yī)療資源嚴(yán)重不足的現(xiàn)象越發(fā)明顯。尋求一種安全、簡單、經(jīng)濟(jì)、實(shí)用的產(chǎn)前篩查及診斷方案,對(duì)降低出生缺陷具有重要意義。同時(shí),隨著對(duì)疾病認(rèn)識(shí)的不斷提高,人們對(duì)于臨床疾病的認(rèn)識(shí)逐漸由臨床診斷到分子診斷水平。然而,目前關(guān)于產(chǎn)前診斷的臨床診療還停留在細(xì)胞遺傳診斷水平,遠(yuǎn)遠(yuǎn)不能滿足臨床需求。隨著測序成本的降低,高通量測序技術(shù)(High-throughput sequencing technology)又稱下一代測序技術(shù)(Next generation sequencing,NGS)迅速發(fā)展,使其廣泛臨床應(yīng)用成為可能。高通量測序技術(shù)的迅速發(fā)展,必將導(dǎo)致傳統(tǒng)醫(yī)學(xué)診療模式的改革。探討高通量測序技術(shù)在產(chǎn)前診斷中的臨床應(yīng)用,為建立基于高技術(shù)平臺(tái)的遺傳學(xué)診療新模式提供理論依據(jù)。目前,臨床應(yīng)用相對(duì)廣泛的無創(chuàng)產(chǎn)前檢測技術(shù)(Noninvasive prenatal genetic testing,NIPT),是基于高通量測序技術(shù)的一項(xiàng)產(chǎn)前篩查新技術(shù)。它通過檢測孕婦外周血中存在胎兒游離DNA(cell-free fetal DNA,cff DNA),檢測胎兒21、18、13染色體非整倍體[1]。前期實(shí)驗(yàn)證實(shí)該技術(shù)具有較高的靈敏度、特異度,但該項(xiàng)技術(shù)對(duì)于傳統(tǒng)產(chǎn)前診斷技術(shù)的影響尚需要進(jìn)一步證實(shí)[2]。如何將該技術(shù)應(yīng)用到臨床,尚需要大樣本前瞻性研究。近年來,臨床對(duì)流產(chǎn)組織以及羊水細(xì)胞遺傳學(xué)檢測需求越來越多。隨著越來越多的染色體微缺失、微重復(fù)等染色體結(jié)構(gòu)異常的臨床意義被進(jìn)一步證實(shí),其可能是導(dǎo)致發(fā)育異常以及智力低下等重大出生缺陷的主要原因之一。全基因組拷貝數(shù)變異分析(Copy number variations,CNVs),作為一種新的遺傳學(xué)標(biāo)記物,在產(chǎn)前診斷領(lǐng)域臨床中的應(yīng)用尚在研究階段。近期研究發(fā)現(xiàn),一旦CNVs涉及重要的基因,就可能導(dǎo)致胚胎生理功能缺陷和相關(guān)疾病的發(fā)生[3]。染色體微結(jié)構(gòu)異常檢測成為近年來人們關(guān)注的熱點(diǎn)。關(guān)于CNVs檢測在流產(chǎn)物、羊水細(xì)胞方面研究較少,缺乏臨床研究數(shù)據(jù)。隨著越來越多有明確臨床意義的CNVs被證實(shí),NGS-CNVs檢測有望成為臨床遺傳檢測新技術(shù)。方法本研究選取2012年1月至2014年1月來唐山市婦幼保健院就診的6005例高危孕婦為研究對(duì)象,依據(jù)不同的產(chǎn)前診斷方案分為兩組:傳統(tǒng)的產(chǎn)前診斷方案組(A組)和聯(lián)合NIPT產(chǎn)前診斷方案組(B組)。比較了兩種方案在產(chǎn)前診斷臨床應(yīng)用對(duì)胎兒染色體異常的檢出效率;分析了孕婦選擇產(chǎn)前診斷率,21-三體、18-三體和13-三體檢出率等相關(guān)指標(biāo);分析了NIPT靈敏度、特異度、假陽性率、陽性預(yù)測值等相關(guān)指標(biāo);建立了將NIPT技術(shù)與傳統(tǒng)的產(chǎn)前篩查及診斷技術(shù)相結(jié)合的聯(lián)合NIPT產(chǎn)前診斷方案,并將該方案應(yīng)用于產(chǎn)前篩查高危人群檢測胎兒染色體異常,評(píng)價(jià)了該方案的臨床應(yīng)用價(jià)值。選取2015年6月至2015年12月在唐山市婦幼保健院產(chǎn)前診斷中心確診為稽留流產(chǎn),流產(chǎn)原因不明,要求遺傳學(xué)檢測的患者105例為研究對(duì)象,對(duì)流產(chǎn)物樣本同時(shí)進(jìn)行了傳統(tǒng)染色體核型分析和基于高通量測序技術(shù)的CNVs檢測(NGS-CNVs)。探討了CNVs技術(shù)在流產(chǎn)物臨床遺傳學(xué)診斷中的應(yīng)用價(jià)值;分析了將該技術(shù)臨床應(yīng)用于現(xiàn)有的遺傳學(xué)檢測流程的可行性。選取2015年6月至2015年12月因各種高危因素來唐山市婦幼保健院產(chǎn)前診斷中心就診,要求羊水穿刺產(chǎn)前診斷的孕婦為研究對(duì)象。在對(duì)孕婦實(shí)施羊水穿刺術(shù),細(xì)胞培養(yǎng)染色體核型分析的同時(shí),留取部分羊水樣本行NGS-CNVs檢測,探討了該技術(shù)在產(chǎn)前診斷中的臨床應(yīng)用價(jià)值。為建立基于高技術(shù)平臺(tái)的臨床診療新模式提供科學(xué)依據(jù)。結(jié)果1、與傳統(tǒng)的產(chǎn)前診斷方案相比,聯(lián)合NIPT產(chǎn)前診斷方案能夠使更多的孕婦接受進(jìn)一步的產(chǎn)前檢測,放棄進(jìn)一步產(chǎn)前診斷的孕婦明顯減少(81.0%vs13.9%,p0.001),差異具有統(tǒng)計(jì)學(xué)意義;聯(lián)合NIPT產(chǎn)前診斷方案,21-三體、18-三體和13-三體的檢出率明顯提高(0.4%vs1.0%,p=0.01)。NIPT檢測胎兒21、18、13號(hào)染色體非整倍體具有高度敏感性、特異性。NIPT檢測21-三體、18-三體和13-三體的靈敏度、特異度分別為100%、99.9%、99.9%,陽性預(yù)測值分別為100%、83.3%和50.0%,假陽性率為0%、0.04%和0.04%。2、NGS-CNVs在流產(chǎn)物遺傳學(xué)檢測中的臨床應(yīng)用結(jié)果表明:NGS-CNVs與絨毛細(xì)胞培養(yǎng)染色體核型分析技術(shù)比較,NGS-CNVs檢測成功率明顯高于染色體核型分析,差異有統(tǒng)計(jì)學(xué)意義,(p0.001)。絨毛細(xì)胞培養(yǎng)染色體分析能檢測出更多的染色體平衡易位,差異具有統(tǒng)計(jì)學(xué)意義,(p0.001);臨床應(yīng)用NGS-CNVs技術(shù)檢測染色體非整倍體,結(jié)果與絨毛細(xì)胞培養(yǎng)染色體核型分析結(jié)果一致。與染色體核型分析相比,NGS-CNVs檢測能夠發(fā)現(xiàn)更多的染色體微結(jié)構(gòu)異常,差異具有統(tǒng)計(jì)學(xué)意義,(p0.001)。3、NGS-CNVs在產(chǎn)前診斷中的臨床應(yīng)用表明:NGS-CNVs與羊水細(xì)胞染色體核型分析技術(shù)相比,染色體核型分析能夠檢測到更多的平衡易位、臂間倒位等染色體結(jié)構(gòu)異常,差異具有統(tǒng)計(jì)學(xué)意義,(p0.001);NGS-CNVs檢測出更多的染色體微結(jié)構(gòu)異常,差異具有統(tǒng)計(jì)學(xué)意義,(p0.001);分析CNVs陽性結(jié)果與羊水穿刺指征的關(guān)系顯示,產(chǎn)前超聲檢查異常與CNVs陽性密切相關(guān)。結(jié)論1、NIPT技術(shù)能夠快速、準(zhǔn)確、非侵入性檢測21、18、13號(hào)染色體非整倍體,更容易被孕婦接受。將NIPT作為傳統(tǒng)產(chǎn)前診斷技術(shù)的有效補(bǔ)充,合理的將該技術(shù)與現(xiàn)有的產(chǎn)前診斷技術(shù)相結(jié)合,聯(lián)合NIPT產(chǎn)前診斷方案切實(shí)可行。聯(lián)合NIPT產(chǎn)前診斷方案,使更多的高危孕婦參與了進(jìn)一步產(chǎn)前檢測,在不影響侵入性產(chǎn)前診斷率的同時(shí),檢測出更多的染色體病患兒,有效的降低了出生缺陷,是較為經(jīng)濟(jì)實(shí)用的產(chǎn)前診斷方案。2、基于高通量測序的NIPT技術(shù),對(duì)于檢測胎兒21、18、13號(hào)染色體非整倍體,具有高度的準(zhǔn)確性。NIPT對(duì)于檢測21-三體、18-三體和13-三體靈敏度、特異度分別為100%、99.9%和99.9%,陽性預(yù)測值分別為100%、83.3%和50.0%,假陽性率分別為0%、0.04%和0.04%。3、NGS-CNVs檢測用于流產(chǎn)物、羊水細(xì)胞染色體微缺失、微重復(fù)的遺傳學(xué)檢測切實(shí)可行,能夠快速、準(zhǔn)確的發(fā)現(xiàn)常見的染色體異常,顯著縮短了檢測周期。NGS-CNVs檢測染色體非整倍體結(jié)果與染色體核型分析結(jié)果一致。NGS-CNVs能夠檢出不能通過常規(guī)染色體核型分析方法發(fā)現(xiàn)的,具有明確臨床意義的染色體微結(jié)構(gòu)異常,提高了遺傳學(xué)檢測水平。NGS-CNVs發(fā)現(xiàn)大量致病性未知的微失衡,其臨床意義有待進(jìn)一步證實(shí)。分析CNVs與羊水穿刺指征的關(guān)系顯示,產(chǎn)前超聲檢查異常與CNVs陽性密切相關(guān)。4、高通量測序在產(chǎn)前篩查及診斷領(lǐng)域臨床應(yīng)用具有較大的發(fā)展空間,與傳統(tǒng)的細(xì)胞培養(yǎng)染色體核型分析、產(chǎn)前超聲、產(chǎn)前篩查及診斷技術(shù)相結(jié)合,能更好的發(fā)揮降低出生缺陷的作用。
[Abstract]:Objective China is one of the countries with high incidence of birth defects, which brings heavy economic burden to the family and the whole society. How to carry out effective prenatal diagnosis and reduce birth defects has always been a hot spot in the field of prenatal diagnosis. Based on genetic counseling and using modern biology, biochemistry, immunogenetics, cytogenetics, molecular genetics and other techniques, we can diagnose whether the fetus has genetic defects and congenital malformations by maternal examination or direct detection of the embryo/fetus. It is important to find a safe, simple, economical and practical prenatal screening and diagnosis scheme to reduce birth defects. At the same time, with the continuous improvement of the understanding of the disease, people's understanding of clinical diseases has gradually changed from clinical diagnosis to molecular diagnosis. At present, the clinical diagnosis and treatment of prenatal diagnosis is still at the level of cellular genetic diagnosis, which is far from meeting the clinical needs. To explore the clinical application of high-throughput sequencing in prenatal diagnosis and to provide theoretical basis for the establishment of a new genetic diagnosis and treatment model based on high-tech platform. E-prenatal genetic testing (NIPT) is a new prenatal screening technology based on high-throughput sequencing technology. It detects fetal aneuploidy of chromosome 21, 18 and 13 by detecting the presence of fetal free DNA (cff DNA) in maternal peripheral blood. In recent years, there is an increasing demand for cytogenetic testing of abortion tissues and amniotic fluid. With the increasing number of chromosomal microdeletions, microduplication and other chromosomal abnormalities, the clinical application of this technique needs a large sample of prospective studies. The clinical significance has been further confirmed that it may be one of the main causes of major birth defects such as developmental abnormalities and mental retardation. As a new genetic marker, whole-genome copy number variations (CNVs) are still in the research stage of clinical application in prenatal diagnosis. Once CNVs involve important genes, it may lead to embryonic physiological defects and related diseases [3]. Detection of chromosomal microstructural abnormalities has become a hot topic in recent years. It has been proved that NGS-CNVs test is expected to become a new clinical genetic testing technology. Methods 6005 high-risk pregnant women who came to Tangshan Maternal and Child Health Hospital from January 2012 to January 2014 were selected as the study subjects. According to different prenatal diagnosis schemes, they were divided into two groups: the traditional prenatal diagnosis scheme group (group A) and the combined NIPT prenatal diagnosis scheme group (group B). The detection efficiency of the two schemes in prenatal diagnosis of fetal chromosomal abnormalities was compared; the prenatal diagnosis rate, 21-trisomy, 18-trisomy and 13-trisomy detection rate were analyzed; the NIPT sensitivity, specificity, false positive rate, positive predictive value and other related indicators were analyzed; the NIPT technology and the traditional NIPT technology were established. The combination of prenatal screening and diagnostic techniques with NIPT prenatal diagnosis program was applied to prenatal screening of high-risk groups for fetal chromosomal abnormalities, and the clinical value of the program was evaluated. In this study, 105 patients with abortion were asked to undergo both conventional chromosome karyotype analysis and high-throughput sequencing-based CNVs (NGS-CNVs). The application value of CNVs in clinical genetic diagnosis of abortion was discussed, and the clinical application of this technique in current genetic testing was analyzed. Feasibility of the test procedure. From June 2015 to December 2015, pregnant women who came to Tangshan Maternal and Child Health Hospital for prenatal diagnosis due to various high-risk factors were selected as the study subjects. Results 1. Compared with the traditional prenatal diagnosis scheme, the combined NIPT prenatal diagnosis scheme can make more pregnant women accept further prenatal testing and give up further prenatal diagnosis. The detection rate of 21-trisomy, 18-trisomy and 13-trisomy in combination with NIPT was significantly increased (0.4% vs 1.0%, P = 0.01). NIPT was highly sensitive and specific in detecting fetal chromosome 21, 18, 13 aneuploidy. The specificity was 100%, 99.9%, 99.9%, the positive predictive value was 100%, 83.3% and 50.0%, the false positive rate was 0%, 0.04% and 0.04%. The difference was statistically significant (p0.001). Chromosome analysis of villous cell culture could detect more balanced chromosome translocations, and the difference was statistically significant (p0.001); NGS-CNVs technique was used to detect chromosomal aneuploidy, and the results were consistent with the karyotype analysis of villous cell culture. Compared with amniotic fluid cell karyotype analysis, NGS-CNVs can detect more balanced translocation, inter-arm inversion and other chromosomal abnormalities. There was statistical significance (p0.001); NGS-CNVs detected more chromosomal microstructural abnormalities, the difference was statistically significant (p0.001); analysis of the relationship between positive results of CNVs and amniocentesis indications showed that prenatal ultrasound abnormalities were closely related to CNVs positive. Conclusion 1, NIPT technology can be rapid, accurate, non-invasive detection of 21, 18, 13 infections. Chromosome aneuploidy is easier to be accepted by pregnant women. NIPT is an effective complement to traditional prenatal diagnosis technology. It is feasible to combine NIPT with prenatal diagnosis technology reasonably. The combination of NIPT with prenatal diagnosis program will enable more high-risk pregnant women to participate in further prenatal testing without affecting invasion. It is an economical and practical prenatal diagnosis scheme. 2. NIPT based on high-throughput sequencing has high accuracy in detecting fetal chromosome 21, 18, 13 aneuploidy. NIPT is used to detect 21-trisomy, 18-trisomy and 13-trisomy. The sensitivity, specificity, positive predictive value were 100%, 99.9% and 99.9%, respectively. The positive predictive value was 100%, 83.3% and 50.0%, false positive rate was 0%, 0.04% and 0.04% respectively. NGS-CNVs can detect chromosomal microstructural abnormalities which can not be detected by conventional chromosomal karyotype analysis methods. NGS-CNVs can improve the level of genetic detection. NGS-CNVs can detect a large number of microimbalances with unknown pathogenicity. Analysis of the relationship between CNVs and amniocentesis indicated that prenatal ultrasound abnormalities were closely related to CNVs positive. 4. High-throughput sequencing has great potential for clinical application in prenatal screening and diagnosis. Combining technology with breaking technology can play a better role in reducing birth defects.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R714.5
[Abstract]:Objective China is one of the countries with high incidence of birth defects, which brings heavy economic burden to the family and the whole society. How to carry out effective prenatal diagnosis and reduce birth defects has always been a hot spot in the field of prenatal diagnosis. Based on genetic counseling and using modern biology, biochemistry, immunogenetics, cytogenetics, molecular genetics and other techniques, we can diagnose whether the fetus has genetic defects and congenital malformations by maternal examination or direct detection of the embryo/fetus. It is important to find a safe, simple, economical and practical prenatal screening and diagnosis scheme to reduce birth defects. At the same time, with the continuous improvement of the understanding of the disease, people's understanding of clinical diseases has gradually changed from clinical diagnosis to molecular diagnosis. At present, the clinical diagnosis and treatment of prenatal diagnosis is still at the level of cellular genetic diagnosis, which is far from meeting the clinical needs. To explore the clinical application of high-throughput sequencing in prenatal diagnosis and to provide theoretical basis for the establishment of a new genetic diagnosis and treatment model based on high-tech platform. E-prenatal genetic testing (NIPT) is a new prenatal screening technology based on high-throughput sequencing technology. It detects fetal aneuploidy of chromosome 21, 18 and 13 by detecting the presence of fetal free DNA (cff DNA) in maternal peripheral blood. In recent years, there is an increasing demand for cytogenetic testing of abortion tissues and amniotic fluid. With the increasing number of chromosomal microdeletions, microduplication and other chromosomal abnormalities, the clinical application of this technique needs a large sample of prospective studies. The clinical significance has been further confirmed that it may be one of the main causes of major birth defects such as developmental abnormalities and mental retardation. As a new genetic marker, whole-genome copy number variations (CNVs) are still in the research stage of clinical application in prenatal diagnosis. Once CNVs involve important genes, it may lead to embryonic physiological defects and related diseases [3]. Detection of chromosomal microstructural abnormalities has become a hot topic in recent years. It has been proved that NGS-CNVs test is expected to become a new clinical genetic testing technology. Methods 6005 high-risk pregnant women who came to Tangshan Maternal and Child Health Hospital from January 2012 to January 2014 were selected as the study subjects. According to different prenatal diagnosis schemes, they were divided into two groups: the traditional prenatal diagnosis scheme group (group A) and the combined NIPT prenatal diagnosis scheme group (group B). The detection efficiency of the two schemes in prenatal diagnosis of fetal chromosomal abnormalities was compared; the prenatal diagnosis rate, 21-trisomy, 18-trisomy and 13-trisomy detection rate were analyzed; the NIPT sensitivity, specificity, false positive rate, positive predictive value and other related indicators were analyzed; the NIPT technology and the traditional NIPT technology were established. The combination of prenatal screening and diagnostic techniques with NIPT prenatal diagnosis program was applied to prenatal screening of high-risk groups for fetal chromosomal abnormalities, and the clinical value of the program was evaluated. In this study, 105 patients with abortion were asked to undergo both conventional chromosome karyotype analysis and high-throughput sequencing-based CNVs (NGS-CNVs). The application value of CNVs in clinical genetic diagnosis of abortion was discussed, and the clinical application of this technique in current genetic testing was analyzed. Feasibility of the test procedure. From June 2015 to December 2015, pregnant women who came to Tangshan Maternal and Child Health Hospital for prenatal diagnosis due to various high-risk factors were selected as the study subjects. Results 1. Compared with the traditional prenatal diagnosis scheme, the combined NIPT prenatal diagnosis scheme can make more pregnant women accept further prenatal testing and give up further prenatal diagnosis. The detection rate of 21-trisomy, 18-trisomy and 13-trisomy in combination with NIPT was significantly increased (0.4% vs 1.0%, P = 0.01). NIPT was highly sensitive and specific in detecting fetal chromosome 21, 18, 13 aneuploidy. The specificity was 100%, 99.9%, 99.9%, the positive predictive value was 100%, 83.3% and 50.0%, the false positive rate was 0%, 0.04% and 0.04%. The difference was statistically significant (p0.001). Chromosome analysis of villous cell culture could detect more balanced chromosome translocations, and the difference was statistically significant (p0.001); NGS-CNVs technique was used to detect chromosomal aneuploidy, and the results were consistent with the karyotype analysis of villous cell culture. Compared with amniotic fluid cell karyotype analysis, NGS-CNVs can detect more balanced translocation, inter-arm inversion and other chromosomal abnormalities. There was statistical significance (p0.001); NGS-CNVs detected more chromosomal microstructural abnormalities, the difference was statistically significant (p0.001); analysis of the relationship between positive results of CNVs and amniocentesis indications showed that prenatal ultrasound abnormalities were closely related to CNVs positive. Conclusion 1, NIPT technology can be rapid, accurate, non-invasive detection of 21, 18, 13 infections. Chromosome aneuploidy is easier to be accepted by pregnant women. NIPT is an effective complement to traditional prenatal diagnosis technology. It is feasible to combine NIPT with prenatal diagnosis technology reasonably. The combination of NIPT with prenatal diagnosis program will enable more high-risk pregnant women to participate in further prenatal testing without affecting invasion. It is an economical and practical prenatal diagnosis scheme. 2. NIPT based on high-throughput sequencing has high accuracy in detecting fetal chromosome 21, 18, 13 aneuploidy. NIPT is used to detect 21-trisomy, 18-trisomy and 13-trisomy. The sensitivity, specificity, positive predictive value were 100%, 99.9% and 99.9%, respectively. The positive predictive value was 100%, 83.3% and 50.0%, false positive rate was 0%, 0.04% and 0.04% respectively. NGS-CNVs can detect chromosomal microstructural abnormalities which can not be detected by conventional chromosomal karyotype analysis methods. NGS-CNVs can improve the level of genetic detection. NGS-CNVs can detect a large number of microimbalances with unknown pathogenicity. Analysis of the relationship between CNVs and amniocentesis indicated that prenatal ultrasound abnormalities were closely related to CNVs positive. 4. High-throughput sequencing has great potential for clinical application in prenatal screening and diagnosis. Combining technology with breaking technology can play a better role in reducing birth defects.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R714.5
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