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Article(id=1203053372141171103, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203053366290113441, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2023.03.0311, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1655395200000, receivedDateStr=2022-06-17, revisedDate=null, revisedDateStr=null, acceptedDate=1663689600000, acceptedDateStr=2022-09-21, onlineDate=1764759875569, onlineDateStr=2025-12-03, pubDate=1679932800000, pubDateStr=2023-03-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764759875569, onlineIssueDateStr=2025-12-03, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764759875569, creator=13701087609, updateTime=1764759875569, updator=13701087609, issue=Issue{id=1203053366290113441, tenantId=1146029695717560320, journalId=1189873630562394117, year='2023', volume='48', issue='3', pageStart='245', pageEnd='366', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1764759874174, creator=13701087609, updateTime=1764810242575, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1203264626747220064, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203053366290113441, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1203264626747220065, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203053366290113441, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=311, endPage=317, ext={EN=ArticleExt(id=1203053372476715444, articleId=1203053372141171103, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Application of chromosome microarray detection and full exome sequencing technique in fetuses with increased nuchal translucency, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the clinical application value of chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in fetuses with increased nuchal translucency (NT). Methods From January 2020 to April 2022, clinical data of 1013 fetuses were collected who underwent invasive prenatal diagnosis due to NT thickening [defined as NT ≥95th centile for the crown-rump length (CRL)] in the Third Affiliated Hospital of Zhengzhou University. All fetuses were undergone CMA detection, 49 fetuses with negative CMA results underwent further prenatal WES. According to NT value, fetuses were divided into the following four groups: <3.5 mm group (529 cases, 21 cases underwent WES), 3.5-4.5 mm group (273 cases, 8 cases underwent WES), 4.5-5.5 mm group (98 cases, 7 cases underwent WES), and ≥5.5 mm group (113 cases, 13 cases underwent WES). According to the results of ultrasound examination, all fetuses were divided into structural malformation group (88 cases, 23 cases underwent WES) and isolated increased NT group (925 cases, 26 cases underwent WES). The possible chromosomal anomalies were analyzed by CMA first. Furthermore, 49 cases with increased NT but negative CMA results were investigated by WES, and the outcomes were followed up. Results CMA showed that, among the 1013 cases of NT thickened fetus, 224 cases (22.1%) of causative genetic defects were detected, including 182 (18.0%) cases with chromosomal aneuploidy and 42 (4.1%) cases with pathogenic copy number variation (pCNVs). Among different NT value groups, the positive rate of CMA in NT ≥5.5 mm group was the highest (47.8%). In addition, the positive rate of CMA in fetuses with increased NT and structural malformations was higher than in isolated increased NT (45.5% vs. 19.9%). WES detected monogenic disease in 5 of 49 fetuses (10.2%) with increased NT and negative CMA results, including 3 cases of autosomal dominant disease, 1 case of autosomal recessive hereditary disease and 1 case of X-linked recessive hereditary disease. All the five fetuses had structural malformations, two of them with increased NT <3.5 mm, and only one of them was born alive. Conclusion WES can detect out monogenic disease in fetuses with increased NT combined structural malformations with negative CMA results. Fetuses with increased NT should also be alert for the possibility of monogenic disease even if the NT value less than 3.5 mm.

, correspAuthors=Shi-Hong Cui, authorNote=null, correspAuthorsNote=
* E-mail:
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目的 探讨染色体微阵列检测技术（CMA）和全外显子组分析（WES）对颈项透明层（NT）增厚胎儿的临床应用价值。方法 收集2020年1月-2022年4月于郑州大学第三附属医院因NT增厚[≥相同头臀长（CRL）胎儿的95% NT值]行侵入性产前诊断的胎儿1013例，所有胎儿均行CMA检测，其中49例CMA结果阴性的胎儿进一步行产前WES。根据NT值将所有胎儿分为以下4组：<3.5 mm（n=529，行WES者21例）、3.5~4.5 mm（n=273，行WES者8例）、4.5~5.5 mm（n=98，行WES者7例）、≥5.5 mm（n=113，行WES者13例）组；再根据超声检查是否合并结构畸形将所有胎儿分为结构畸形组（n=88，行WES者23例）与单纯性NT增厚组（n=925，行WES者26例）。分析1013例胎儿的染色体异常检出率；对行WES的49例胎儿分析其WES检测结果，并随访妊娠结局。结果 CMA检测结果显示，在1013例NT增厚胎儿中共检出224例（22.1%）染色体异常，其中182例为染色体非整倍体，42例为致病性拷贝数变异（p/Lp CNVs）。在不同NT厚度的分组中，CMA在NT≥5.5 mm组的染色体异常检出率最高（47.8%，54/113）；另外，结构畸形组的CMA阳性检出率（45.5%，40/88）高于单纯性NT增厚组（19.9%，184/925）。WES检测结果显示，在49例CMA结果阴性的NT增厚胎儿中检出5例（10.2%）单基因疾病，包括3例常染色体显性遗传病、1例常染色体隐性遗传病和1例X染色体连锁隐性遗传病，5例胎儿均伴有结构畸形；5例中2例胎儿的NT值<3.5 mm；5例胎儿中，仅1例活产。结论 WES可在CMA结果阴性的、合并结构畸形的NT增厚胎儿中检出单基因遗传病；NT值<3.5 mm的NT增厚胎儿也应警惕合并单基因遗传病的可能。

, correspAuthors=崔世红, authorNote=null, correspAuthorsNote=
崔世红，E-mail：
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孙媛媛，硕士研究生，主要从事产前诊断方面的研究

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孙媛媛，硕士研究生，主要从事产前诊断方面的研究

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孙媛媛，硕士研究生，主要从事产前诊断方面的研究

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J Transl Med, 2022, 20(1): 10., articleTitle=Clinical efficiency of simultaneous CNV-seq and whole-exome sequencing for testing fetal structural anomalies, refAbstract=null)], funds=[Fund(id=1203053377887367870, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, awardId=202102310388, language=EN, fundingSource=Science and Technology Development Projects of Henan(202102310388), fundOrder=null, country=null), Fund(id=1203053377979642563, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, awardId=202102310388, language=CN, fundingSource=河南省2020年科技发展计划(202102310388), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1203053373219107304, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, xref=null, ext=[AuthorCompanyExt(id=1203053373227495913, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, companyId=1203053373219107304, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Henan Provincial Clinical Research Center for Perinatal Medicine/Prenatal Diagnosis Center, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China), AuthorCompanyExt(id=1203053373235884522, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, companyId=1203053373219107304, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=河南省妇产疾病（围产医学）临床医学研究中心/郑州大学第三附属医院产前诊断中心，河南郑州 450052)])], figs=[ArticleFig(id=1203053376452915840, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=EN, label=Tab. 1, caption=

Chromosomal abnormalities detected by CMA in different NT thickness groups [n(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
NT厚度T21T18T13T9XOXXYp/Lp CNVs合计[n(%)]
<3.5 mm (n=529)44(8.3)5(0.9)3(0.6)1(0.2)2(0.4)4(0.8)24(4.5)83(15.7)
3.5~4.5 mm (n=273)35(12.8)4(1.5)2(0.7)03(1.1)3(1.1)10(4.4)57(20.9)
4.5~5.5 mm (n=98)19(19.4)3(3.1)3(3.1)2(2.1)1(1.0)02(2.0)30(30.6)
≥5.5 mm (n=113)16(14.2)12(10.7)2(1.8)018(15.9)06(5.3)54(47.8)
合计(n=1013)114(11.3)24(2.4)10(1.0)3(0.3)24(2.4)7(0.7)42(4.1)224(22.1)
), ArticleFig(id=1203053376540996231, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=CN, label=表1, caption=

不同NT厚度分组中CMA检出的染色体异常[例(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
NT厚度T21T18T13T9XOXXYp/Lp CNVs合计[n(%)]
<3.5 mm (n=529)44(8.3)5(0.9)3(0.6)1(0.2)2(0.4)4(0.8)24(4.5)83(15.7)
3.5~4.5 mm (n=273)35(12.8)4(1.5)2(0.7)03(1.1)3(1.1)10(4.4)57(20.9)
4.5~5.5 mm (n=98)19(19.4)3(3.1)3(3.1)2(2.1)1(1.0)02(2.0)30(30.6)
≥5.5 mm (n=113)16(14.2)12(10.7)2(1.8)018(15.9)06(5.3)54(47.8)
合计(n=1013)114(11.3)24(2.4)10(1.0)3(0.3)24(2.4)7(0.7)42(4.1)224(22.1)
), ArticleFig(id=1203053376620688011, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=EN, label=Tab. 2, caption=

Results of pathogenicity copy number variation in 42 NT thickened fetuses

, figureFileSmall=null, figureFileBig=null, tableContent=
编号NT (mm)p/Lp CNVs检出结果
13.322q11.21(18,648,856-21,800,471)x1
24.022q11.21(18,919,478-21,800,471)x3
33.02q31.1q32.1(176,981,701-185,780,793)x1
44.03q26.1q26.31(161,775,444-175,196,854)x1
56.822q11.21(18,648,856-21,800,471)x1
63.48p23.1(6,999,220-11,935,465)x3
73.2Xp22.33(2,693,466-3,553,923)x1
83.8Xq27.3q28(146,832,539-147,329,938)x0
93.016p11.2(28,441,548-29,342,193)x1
105.816p11.2(29,580,021-30,190,029)x1
114.016q22.1(66,900,623-67,853,396)x1
126.422q11.21(18,636,750-21,800,471)x1
132.517p12(14,196,248-15,579,519)x1
143.18p23.3p23.1(208,049-6,825,724)x1
154.47p22.1(5,909,218-6,016,035)x1
163.216p11.2(29,417,211-30,178,708)x1
172.51q21.1q21.2(146,242,158-148,413,447)x1
182.7]Xp11.23p11.22(49,015,621-53,975,906)x2
194.57q32.1q34(129293926_139507672)x1
2011.9Xp22.33p11.23(251888_49047738)x1
213.415q11.2(22582283_23060000)x1
223.26q11.1q12(61794464_67698551)x1
233.415q11.2(22582283_23102621)x1
243.35q14.3(86591430_91366505)x1
253.115q11.2(22582283_23102621)x1
263.215q11.2(22582283_23370622)x1
275.422q11.21(18929330_21110475)x1
284.115q11.2(22582283_23102621)x1
294.316p13.11p12.3(15225421_18148856)x1
302.36q26q27(162941342_170605209)x1
314.310q26.2q26.3(126155615_133612882)x1
325.53q24q29(148368251_198124573)x3
333.115q11.2(22582283_23102621)x1
343.015q25.2(82399279_84542090)x1
352.87q36.3(157267581_159327017)x1
363.918q22.1q23(68568042_80255845)x1
373.19p24.3p23(208455_13615462)x1
383.0Xp22.31(6531712_8167604)x1
394.0Xp21.1(31761327_32144474)x0
403.315q11.2(22582283_23060000)x1
413.315q11.2(22582283_23060000)x1
425.87q11.22q21.11(68,215,938-77,708,307)x1
), ArticleFig(id=1203053376729739920, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=CN, label=表2, caption=

42例NT增厚胎儿p/Lp CNVs检出结果

, figureFileSmall=null, figureFileBig=null, tableContent=
编号NT (mm)p/Lp CNVs检出结果
13.322q11.21(18,648,856-21,800,471)x1
24.022q11.21(18,919,478-21,800,471)x3
33.02q31.1q32.1(176,981,701-185,780,793)x1
44.03q26.1q26.31(161,775,444-175,196,854)x1
56.822q11.21(18,648,856-21,800,471)x1
63.48p23.1(6,999,220-11,935,465)x3
73.2Xp22.33(2,693,466-3,553,923)x1
83.8Xq27.3q28(146,832,539-147,329,938)x0
93.016p11.2(28,441,548-29,342,193)x1
105.816p11.2(29,580,021-30,190,029)x1
114.016q22.1(66,900,623-67,853,396)x1
126.422q11.21(18,636,750-21,800,471)x1
132.517p12(14,196,248-15,579,519)x1
143.18p23.3p23.1(208,049-6,825,724)x1
154.47p22.1(5,909,218-6,016,035)x1
163.216p11.2(29,417,211-30,178,708)x1
172.51q21.1q21.2(146,242,158-148,413,447)x1
182.7]Xp11.23p11.22(49,015,621-53,975,906)x2
194.57q32.1q34(129293926_139507672)x1
2011.9Xp22.33p11.23(251888_49047738)x1
213.415q11.2(22582283_23060000)x1
223.26q11.1q12(61794464_67698551)x1
233.415q11.2(22582283_23102621)x1
243.35q14.3(86591430_91366505)x1
253.115q11.2(22582283_23102621)x1
263.215q11.2(22582283_23370622)x1
275.422q11.21(18929330_21110475)x1
284.115q11.2(22582283_23102621)x1
294.316p13.11p12.3(15225421_18148856)x1
302.36q26q27(162941342_170605209)x1
314.310q26.2q26.3(126155615_133612882)x1
325.53q24q29(148368251_198124573)x3
333.115q11.2(22582283_23102621)x1
343.015q25.2(82399279_84542090)x1
352.87q36.3(157267581_159327017)x1
363.918q22.1q23(68568042_80255845)x1
373.19p24.3p23(208455_13615462)x1
383.0Xp22.31(6531712_8167604)x1
394.0Xp21.1(31761327_32144474)x0
403.315q11.2(22582283_23060000)x1
413.315q11.2(22582283_23060000)x1
425.87q11.22q21.11(68,215,938-77,708,307)x1
), ArticleFig(id=1203053376847180439, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=EN, label=Tab. 3, caption=

WES results and pregnancy outcomes of 49 fetuses with increased NT and normal CMA results (n)

, figureFileSmall=null, figureFileBig=null, tableContent=
NT厚度(mm)NT增厚合并结构畸形p/Lp SNVs妊娠结局
TOPLB
<3.5 (n=21)132129
3.5~4.5 (n=8)4344
4.5~5.5 (n=7)3043
≥5.5 (n=13)30112
), ArticleFig(id=1203053377031729822, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=CN, label=表3, caption=

49例CMA结果正常NT增厚胎儿的WES检测结果及妊娠结局(例)

, figureFileSmall=null, figureFileBig=null, tableContent=
NT厚度(mm)NT增厚合并结构畸形p/Lp SNVs妊娠结局
TOPLB
<3.5 (n=21)132129
3.5~4.5 (n=8)4344
4.5~5.5 (n=7)3043
≥5.5 (n=13)30112
), ArticleFig(id=1203053377149170339, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=EN, label=Tab. 4, caption=

Results of 5 cases NT thickenedfetuses with monogenic diseases

, figureFileSmall=null, figureFileBig=null, tableContent=
编号NT值(CRL)后期超声新增表型基因(OMIM)变异基因杂合性致病性变异来源遗传方式相关疾病(OMIM)妊娠结局
13.8 mm (CRL, 56 mm)双肾肾盂分离，室间隔缺损GPC3 (300037)Xq26.2缺失0.18 kb，覆盖GPC3基因的8号外显子半合子P母亲XLSimpson-Golabi-Behmel综合征1型(312870)活产
23.4 mm (CRL, 71 mm)四肢姿势固定，双下肢肌肉薄，双侧摇椅足，双手姿势异常，室间隔缺损ERCC2 (126340)c.2041G>A p.D681N杂合LP父亲AR脑-眼-面-骨骼综合征2型(610756)引产
c.1885C>T: p.Q629*杂合P新发
32.5 mm (CRL, 63 mm)小头畸形，透明隔腔早闭，骨发育不良COL1A1 (120150)c.2362G>A: p.G788S杂合LP新发AD成骨不全Ⅱ型(166210)引产
43.8 mm (CRL, 56 mm)颈部皮肤皱褶增厚，肾脏异常，室间隔缺损RAF1 (164760)c.770C>T: (p.S257L)杂合P新发ADNoonan综合征5型(611553)引产
53.7 mm (CRL, 63 mm)心脏发育异常，房室瓣异常，静脉导管异常KMT2D (602113)c.10703_10704del:p.T3568Rfs*22杂合P新发ADKabuki综合征1型(147920)引产
), ArticleFig(id=1203053377287582372, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=CN, label=表4, caption=

5例NT增厚胎儿致病性单基因异常结果

, figureFileSmall=null, figureFileBig=null, tableContent=
编号NT值(CRL)后期超声新增表型基因(OMIM)变异基因杂合性致病性变异来源遗传方式相关疾病(OMIM)妊娠结局
13.8 mm (CRL, 56 mm)双肾肾盂分离，室间隔缺损GPC3 (300037)Xq26.2缺失0.18 kb，覆盖GPC3基因的8号外显子半合子P母亲XLSimpson-Golabi-Behmel综合征1型(312870)活产
23.4 mm (CRL, 71 mm)四肢姿势固定，双下肢肌肉薄，双侧摇椅足，双手姿势异常，室间隔缺损ERCC2 (126340)c.2041G>A p.D681N杂合LP父亲AR脑-眼-面-骨骼综合征2型(610756)引产
c.1885C>T: p.Q629*杂合P新发
32.5 mm (CRL, 63 mm)小头畸形，透明隔腔早闭，骨发育不良COL1A1 (120150)c.2362G>A: p.G788S杂合LP新发AD成骨不全Ⅱ型(166210)引产
43.8 mm (CRL, 56 mm)颈部皮肤皱褶增厚，肾脏异常，室间隔缺损RAF1 (164760)c.770C>T: (p.S257L)杂合P新发ADNoonan综合征5型(611553)引产
53.7 mm (CRL, 63 mm)心脏发育异常，房室瓣异常，静脉导管异常KMT2D (602113)c.10703_10704del:p.T3568Rfs*22杂合P新发ADKabuki综合征1型(147920)引产
), ArticleFig(id=1203053377417605801, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=EN, label=Tab. 5, caption=

WES test results of 2cases with insufficient genetic evidence of pathogenicity

, figureFileSmall=null, figureFileBig=null, tableContent=
编号NT值(CRL)后期超声新增表型OMIM数据库基因变异基因杂合性致病性变异来源遗传方式OMIM数据库相关疾病妊娠结局
63.4 mm (CRL: 74 mm)双肾体积增大并实质回声增强(左肾28 mm×15 mm，右肾26 mm×15 mm)NPHP3 (608002)c.1574C>T: p.P525L杂合VUS父亲AR肾单位肾痨3型(604387)引产
c.514T>A: p.F172I杂合VUS父亲
c.3775C>T: p.R1259*杂合LP母亲
71.9 mm (CRL: 49 mm)–ITGA6 (147556)c.341dup: p.D114Efs*6杂合LP父亲AR交界型大疱性表皮松解症伴幽门狭窄（226730）胎死宫内
c.2031T>G: p.L677L杂合VUS母亲
), ArticleFig(id=1203053377556017839, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=CN, label=表5, caption=

2例致病性遗传证据不足的NT增厚胎儿WES检测结果

, figureFileSmall=null, figureFileBig=null, tableContent=
编号NT值(CRL)后期超声新增表型OMIM数据库基因变异基因杂合性致病性变异来源遗传方式OMIM数据库相关疾病妊娠结局
63.4 mm (CRL: 74 mm)双肾体积增大并实质回声增强(左肾28 mm×15 mm，右肾26 mm×15 mm)NPHP3 (608002)c.1574C>T: p.P525L杂合VUS父亲AR肾单位肾痨3型(604387)引产
c.514T>A: p.F172I杂合VUS父亲
c.3775C>T: p.R1259*杂合LP母亲
71.9 mm (CRL: 49 mm)–ITGA6 (147556)c.341dup: p.D114Efs*6杂合LP父亲AR交界型大疱性表皮松解症伴幽门狭窄（226730）胎死宫内
c.2031T>G: p.L677L杂合VUS母亲
), ArticleFig(id=1203053377652486836, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=EN, label=Tab. 6, caption=

Previous studies on genetic testing of fetuses with increased NT

, figureFileSmall=null, figureFileBig=null, tableContent=
参考文献国家纳入对象的NT截断值检出率(%)
Daum等[22]以色列3.0 mm10.5(2/19)
Lord等[9]英国4.0 mm2.2(2/93)
Petrovski等[10]美国3.5 mm3.4(2/59)
Yang等[23]中国3.5 mm5.5(4/73)
Xue等[24]中国3.5 mm12.5(3/24)
Norton等[25]美国3.5 mm6.7(1/15)
符芳等[26]中国3.5 mm6.3(6/96)
Chen等[27]中国95%th23.5(4/17)
), ArticleFig(id=1203053377765733049, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203053372141171103, language=CN, label=表6, caption=

对NT增厚胎儿行外显子组测序的既往研究

, figureFileSmall=null, figureFileBig=null, tableContent=
参考文献国家纳入对象的NT截断值检出率(%)
Daum等[22]以色列3.0 mm10.5(2/19)
Lord等[9]英国4.0 mm2.2(2/93)
Petrovski等[10]美国3.5 mm3.4(2/59)
Yang等[23]中国3.5 mm5.5(4/73)
Xue等[24]中国3.5 mm12.5(3/24)
Norton等[25]美国3.5 mm6.7(1/15)
符芳等[26]中国3.5 mm6.3(6/96)
Chen等[27]中国95%th23.5(4/17)
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染色体微阵列分析和全外显子组测序技术在颈项透明层增厚胎儿中的应用
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孙媛媛 , 刘灵 , 职云晓 , 崔世红 *
解放军医学杂志 | 临床研究 2023,48(3): 311-317
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解放军医学杂志 | 临床研究 2023, 48(3): 311-317
染色体微阵列分析和全外显子组测序技术在颈项透明层增厚胎儿中的应用
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孙媛媛, 刘灵, 职云晓, 崔世红*
作者信息
  • 河南省妇产疾病（围产医学）临床医学研究中心/郑州大学第三附属医院产前诊断中心，河南郑州 450052

    • 孙媛媛，硕士研究生，主要从事产前诊断方面的研究

通讯作者:

崔世红，E-mail：
Application of chromosome microarray detection and full exome sequencing technique in fetuses with increased nuchal translucency
Yuan-Yuan Sun, Ling Liu, Yun-Xiao Zhi, Shi-Hong Cui*
Affiliations
  • Henan Provincial Clinical Research Center for Perinatal Medicine/Prenatal Diagnosis Center, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
出版时间: 2023-03-28 doi: 10.11855/j.issn.0577-7402.2023.03.0311
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摘要
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目的 探讨染色体微阵列检测技术（CMA）和全外显子组分析（WES）对颈项透明层（NT）增厚胎儿的临床应用价值。方法 收集2020年1月-2022年4月于郑州大学第三附属医院因NT增厚[≥相同头臀长（CRL）胎儿的95% NT值]行侵入性产前诊断的胎儿1013例，所有胎儿均行CMA检测，其中49例CMA结果阴性的胎儿进一步行产前WES。根据NT值将所有胎儿分为以下4组：<3.5 mm（n=529，行WES者21例）、3.5~4.5 mm（n=273，行WES者8例）、4.5~5.5 mm（n=98，行WES者7例）、≥5.5 mm（n=113，行WES者13例）组；再根据超声检查是否合并结构畸形将所有胎儿分为结构畸形组（n=88，行WES者23例）与单纯性NT增厚组（n=925，行WES者26例）。分析1013例胎儿的染色体异常检出率；对行WES的49例胎儿分析其WES检测结果，并随访妊娠结局。结果 CMA检测结果显示，在1013例NT增厚胎儿中共检出224例（22.1%）染色体异常，其中182例为染色体非整倍体，42例为致病性拷贝数变异（p/Lp CNVs）。在不同NT厚度的分组中，CMA在NT≥5.5 mm组的染色体异常检出率最高（47.8%，54/113）；另外，结构畸形组的CMA阳性检出率（45.5%，40/88）高于单纯性NT增厚组（19.9%，184/925）。WES检测结果显示，在49例CMA结果阴性的NT增厚胎儿中检出5例（10.2%）单基因疾病，包括3例常染色体显性遗传病、1例常染色体隐性遗传病和1例X染色体连锁隐性遗传病，5例胎儿均伴有结构畸形；5例中2例胎儿的NT值<3.5 mm；5例胎儿中，仅1例活产。结论 WES可在CMA结果阴性的、合并结构畸形的NT增厚胎儿中检出单基因遗传病；NT值<3.5 mm的NT增厚胎儿也应警惕合并单基因遗传病的可能。

胎儿颈项透明层增厚  /  产前诊断  /  染色体微阵列分析  /  全外显子组测序

Objective To investigate the clinical application value of chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in fetuses with increased nuchal translucency (NT). Methods From January 2020 to April 2022, clinical data of 1013 fetuses were collected who underwent invasive prenatal diagnosis due to NT thickening [defined as NT ≥95th centile for the crown-rump length (CRL)] in the Third Affiliated Hospital of Zhengzhou University. All fetuses were undergone CMA detection, 49 fetuses with negative CMA results underwent further prenatal WES. According to NT value, fetuses were divided into the following four groups: <3.5 mm group (529 cases, 21 cases underwent WES), 3.5-4.5 mm group (273 cases, 8 cases underwent WES), 4.5-5.5 mm group (98 cases, 7 cases underwent WES), and ≥5.5 mm group (113 cases, 13 cases underwent WES). According to the results of ultrasound examination, all fetuses were divided into structural malformation group (88 cases, 23 cases underwent WES) and isolated increased NT group (925 cases, 26 cases underwent WES). The possible chromosomal anomalies were analyzed by CMA first. Furthermore, 49 cases with increased NT but negative CMA results were investigated by WES, and the outcomes were followed up. Results CMA showed that, among the 1013 cases of NT thickened fetus, 224 cases (22.1%) of causative genetic defects were detected, including 182 (18.0%) cases with chromosomal aneuploidy and 42 (4.1%) cases with pathogenic copy number variation (pCNVs). Among different NT value groups, the positive rate of CMA in NT ≥5.5 mm group was the highest (47.8%). In addition, the positive rate of CMA in fetuses with increased NT and structural malformations was higher than in isolated increased NT (45.5% vs. 19.9%). WES detected monogenic disease in 5 of 49 fetuses (10.2%) with increased NT and negative CMA results, including 3 cases of autosomal dominant disease, 1 case of autosomal recessive hereditary disease and 1 case of X-linked recessive hereditary disease. All the five fetuses had structural malformations, two of them with increased NT <3.5 mm, and only one of them was born alive. Conclusion WES can detect out monogenic disease in fetuses with increased NT combined structural malformations with negative CMA results. Fetuses with increased NT should also be alert for the possibility of monogenic disease even if the NT value less than 3.5 mm.

increased nuchal translucency  /  prenatal diagnosis  /  chromosomal microarray analysis  /  whole-exome sequencing
孙媛媛, 刘灵, 职云晓, 崔世红. 染色体微阵列分析和全外显子组测序技术在颈项透明层增厚胎儿中的应用. 解放军医学杂志, 2023 , 48 (3) : 311 -317 . DOI: 10.11855/j.issn.0577-7402.2023.03.0311
Yuan-Yuan Sun, Ling Liu, Yun-Xiao Zhi, Shi-Hong Cui. Application of chromosome microarray detection and full exome sequencing technique in fetuses with increased nuchal translucency[J]. Medical Journal of Chinese People’s Liberation Army, 2023 , 48 (3) : 311 -317 . DOI: 10.11855/j.issn.0577-7402.2023.03.0311
正文
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颈项透明层（nuchal translucency，NT）是11~13+6周孕妇超声筛查的常规项目，目前认为NT增厚与胎儿染色体异常、结构异常（如先天性心脏畸形）和广泛的遗传疾病有关[1-2]。2020年美国妇产科医师学会（American College of Obstetricians and Gynecologists，ACOG）在关于胎儿染色体异常筛查的指南中指出，应对NT增厚病例常规行产前遗传学检测[3]。染色体微阵列分析（chromosome microarray analysis，CMA）是产前诊断的一线选择[4]，在NT增厚胎儿中可检测到20%~30%的染色体异常[5]，但仍有很多NT增厚病例的病因无法用CMA解释，尤其是当合并潜在的单基因遗传病时。全外显子组测序（whole-exome sequencing，WES）为二代测序技术，可进行单基因遗传病的检测[6]，且具有检测范围广、检出率高、检测性价比高等优点[7]，已首先在儿科中成功应用[8]，目前也已被逐渐应用于产前诊断。Lord等[9]和Petrovski等[10]分别在两项规模较大的WES研究中发现，超声提示结构异常胎儿的单基因遗传病诊断率分别为10.0%和8.5%，提示WES可弥补传统产前诊断的不足。2020年美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics，ACMG）发布指南，正式推荐对于超声发现胎儿结构异常且CMA检测结果正常的病例，应进一步行产前外显子组检测以排除胎儿单基因变异[11]。本研究分析因NT增厚行侵入性产前诊断的CMA检测结果，并对CMA结果阴性、进一步行WES检测的结果进行分析，旨在探讨CMA和WES对NT增厚胎儿的临床应用价值。
1 资料与方法
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1.1 研究对象
收集2020年1月-2022年4月因NT增厚于郑州大学第三附属医院行侵入性产前诊断并接受CMA检测的1013例胎儿标本[胎儿标本根据侵入性诊断时的胎龄取自绒毛（n=564）、羊水（n=423）或终止妊娠后通过活检获得的胎儿组织（n=26）]进行回顾性分析。经过充分的遗传咨询后，最终49例CMA检测结果阴性的胎儿父母选择进一步行WES检测，包括34例家系（trio）WES和15例单人WES，trio WES的核心家系成员标本取自外周血。NT增厚诊断标准：孕11~13+6周超声测量胎儿NT厚度，参照英国胎儿医学基金会（Fetal Medicine Foundation of the United Kingdom，FMF）制定的标准[12]，NT≥相同头臀长（crown-rump length，CRL）胎儿的95% NT值时诊断为NT增厚。纳入标准：（1）NT≥相同CRL胎儿的95%NT值；（2）伴或不伴有其他超声结构的异常；（3）进行介入性产前诊断CMA检测；（4）单胎妊娠。排除已知感染或暴露于已知致畸药物的胎儿。根据NT值将1013例胎儿分为4组：<3.5 mm（n=529，行WES者21例）、3.5~4.5 mm（n=273，行WES者8例）、4.5~5.5 mm（n=98，行WES者7例）、≥5.5 mm（n=113，行WES者13例）。根据是否合并结构畸形（如心脏畸形、四肢畸形、内脏反转、肾脏畸形等，不包括单脐动脉、鼻骨缺失等超声软指标）将1013例胎儿分为结构畸形组（n=88，行WES者23例）与单纯性NT增厚组（n=925，行WES者26例）。本研究获郑州大学第三附属医院伦理委员会审批（2022-167-01）。
1.2 方法
1.2.1 全基因组DNA的提取及CMA检测
采用德国Qiagen试剂盒提取标本中的全基因组DNA，所提取的DNA确定无母血污染后进行CMA检测。基因组DNA通过酶切消化、与接头连接、扩增、纯化、生物素标记后，用包含a-CGH和SNP-array探针的CytoScan 750K芯片试剂盒（Affymetrix公司，美国）进行染色体拷贝数变异（copy number variants，CNVs）检测。采用CHAS软件（4.2.80版本）并结合相关数据库（包括DGV数据库、Decipher数据库、OMIM数据库等）进行数据分析。
1.2.2 全外显子组测序
采用WES来识别单基因变异。基因组DNA被提交、杂交和富集，使用Illumina Novaseq6000平台（Illumina，San Diego，美国）对处理后的基因组DNA进行测序分析，使用CASAVA v1.82处理原始数据，将贝瑞基因的Verita Trekker®变异检测系统和第三方软件GATK（http://software.broadinstitute.org/gatk/）用于变异的检出。变异注释及解释由ANNOVAR和贝瑞基因授权的Enliven®Variants Annotation Interpretation System进行。注释数据库主要包括：gnomAD（http://gnomad.broadinstitute.org/）；千人基因组计划（http://browser.1000genomes.org）；Berrybig数据人口数据库：dbSNP（http://www.ncbi.nlm.nih.gov/snp）、SIFT（http://sift.jcvi.org）、MutationAssessor（http://mutationassessor.org）、HPO（https://hpo.jax.org/app/）等。根据ACMG的遗传变异解释指南[13-14]，将变异分为5类：“致病的（pathogenic，P）”“可能致病的（likely pathogenic，LP）”“良性的（benign，B）”“可能良性的（likely benign，LB）”和“意义不明确的变异（variant of uncertain significance，VUS）”。仅将可以解释胎儿表型的P或LP变异归为阳性结果。
1.2.3 指标分析
统计1013例NT增厚胎儿的CMA染色体异常检出结果，并分析不同分组的染色体异常检出率。对进一步行WES的49例胎儿分析其单基因遗传病检出结果，并追踪妊娠结局。
1.3 统计学处理
采用SPSS 26.0软件进行统计分析。计数资料以例（%）表示，两组间比较采用χ2检验。P<0.05为差异有统计学意义。
2 结果
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2.1 1013例NT增厚胎儿的CMA检测结果
CMA在1013例NT增厚胎儿中检出21-三体综合征114例（11.3%）、18-三体综合征24例（2.4%）、13-三体综合征10例（1.0%）、9-三体综合征3例（0.3%）、Turner综合征（45,XO）24例（2.4%）和47,XXY 7例（0.7%）；此外，CMA检出致病性/可能致病性拷贝数变异（p/Lp CNVs）42例（4.1%），具体CMA检测结果见表1，42例NT增厚胎儿p/Lp CNVs检出结果见表2。
2.2 不同分组CMA检测结果分析
CMA检测结果显示，染色体异常检出率随NT厚度的增加而增高，NT≥5.5 mm组的检出率最高（47.8%，54/113）。此外，结构畸形组的CMA阳性检出率（45.5%，40/88）明显高于单纯性NT增厚组（19.9%，184/925），差异有统计学意义（χ2=30.487，P<0.05）。
2.3 WES检测结果
49例CMA结果呈阴性的NT增厚胎儿中，NT厚度<3.5 mm的胎儿21例（合并结构畸形者13例），3.5~4.5 mm的胎儿8例（合并结构畸形者4例），4.5~5.5 mm的7例（合并结构畸形者3例），≥5.5 mm的13例（合并结构畸形者3例）。WES在49例胎儿中检出5例单基因遗传病，5例均合并结构畸形，其中2例NT厚度<3.5 mm，3例NT厚度为3.5~4.5 mm（表3）。WES检出的5例单基因遗传病包括KMT2D、COL1A1、RAF1基因变异所致的3例常染色体显性遗传病，ERCC2基因复合杂合变异所致的1例常染色体隐性遗传病，还有1例在WES范围内检测到X号染色体Xq26.2处有0.18 kb的缺失，覆盖了GPC3基因8号外显子，GPC3基因变异可导致X连锁隐性遗传病Simpson-Golabi-Behmel遗传综合征1型。5例单基因遗传病检出胎儿的后期超声均提示不同程度的结构畸形（室间隔缺损、骨骼发育不良、四肢姿势异常等）。5例胎儿中仅1例顺利分娩。WES阳性检出胎儿的具体临床信息及WES结果见表4。
此外，本研究WES意外检测到2例（例6、例7）与胎儿表型相关但遗传学证据不足的致病性变异。WES在例6胎儿样本中检测到基因NPHP3的3个变异，与常染色体隐性遗传病肾单位肾痨3型（OMIM:604387）相关，该遗传综合征和例6胎儿表型相符的临床特征为囊性肾、肾脏回声增强，但3个变异中仅1个判读为LP，另2个判读为VUS；WES在例7胎儿样本中检测到基因ITGA6的2个变异，与常染色体隐性遗传病交界型大疱性表皮松解症伴幽门狭窄（OMIM:226730）相关，该遗传综合征和例7胎儿表型相符的临床特征为婴儿期夭折，但2个变异中仅1个判读为LP，另1个判读为VUS。这2例胎儿均因遗传学证据不足无法确诊，WES检测结果及胎儿临床信息见表5。
3 讨论
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CMA可在全基因组水平进行染色体异常分析，能检出传统核型分析无法识别的染色体p/Lp CNVs[15]，2013年ACOG已明确将其列为胎儿超声异常产前诊断的首选遗传学检测方法[16]。本研究CMA检出182例（18.0%，182/1013）NT增厚胎儿合并染色体非整倍体，其中21-三体综合征占比最高（11.3%），其次是18-三体综合征（2.4%）、45,X（2.4%）和13-三体综合征（1.0%）；此外，CMA还检出42例（4.1%）NT增厚胎儿合并致病性染色体拷贝数变异，与文献报道[17]相符。本研究CMA检测还发现，合并结构畸形的NT增厚胎儿中染色体异常检出率高于单纯性NT增厚胎儿，在合并结构畸形的NT增厚胎儿CMA阳性检出率高达45.5%，提示CMA在产前诊断中具有重要作用。
除染色体异常外，胎儿NT增厚也与部分遗传综合征有关。CMA无法检测到由单个基因变异所致的遗传综合征，而WES则可进行单基因遗传病的检测。因此，本研究针对CMA结果阴性的49例NT增厚胎儿进一步行WES检测，共检出5例合并单基因遗传病，且这5例的产前超声均检出结构畸形，而单纯性NT增厚组的26例胎儿WES结果均为阴性。以往的研究也发现，妊娠期间单纯性NT增厚的胎儿单基因遗传病阳性率很低[9-10]。Mellis等[18]对Lord等[9]及Petrovski等[10]两项前瞻性队列研究中包含NT增厚胎儿的WES结果进行了Meta分析，结果发现，NT增厚胎儿合并超声结构畸形者的单基因遗传病检出率为37.83%（14/37），远高于单纯性NT增厚者的检出率[1.8%（1/111）]。此外，本研究检出的5例单基因遗传病胎儿中有4例（例1、2、4、5）存在不同类型的心脏畸形，2例（例2、3）合并胎儿生长受限、多发结构异常等骨骼系统畸形，而既往研究也发现，NT增厚与各种心脏畸形、各种骨骼发育不良关系密切[19-20]，对排除了染色体异常的NT增厚胎儿，后续超声检查应重点筛查心脏、骨骼系统畸形，对单基因疾病的检出也有一定意义。
有研究认为，NT值<3.5 mm的NT增厚胎儿，在排除染色体非整倍体后，其围产期不良结局的风险不会明显增加，因此，以往对NT增厚胎儿行WES的研究常用3.5 mm作为纳入对象的NT截断值[21]。本研究选择相同CRL胎儿第95个百分位数NT值作为纳入的NT截断值，结果发现，WES检测出的5例单基因疾病中，2例NT值<3.5 mm：例2的NT厚度为3.4 mm，例3的NT厚度为2.5 mm。因此，以3.5 mm作为WES检测的NT截断值可能并不合理。对于NT值较小的NT增厚胎儿，排除染色体异常后，仍应密切监测其超声检查结果，警惕合并单基因疾病的可能。
胎儿的妊娠结局及临床干预直接受相应WES阳性诊断的影响。本研究5例单基因疾病中，4例胎儿测序结果提示存在严重致死性单基因遗传病，其父母选择终止妊娠。1例胎儿的WES检测结果提示可能合并Simpson-Golabi-Behmel综合征1型，此遗传综合征主要表型有腹股沟疝、隐睾、尿道下裂、肾脏增大等，可出生后治疗。经过慎重考虑，胎儿父母选择妊娠，并最终在37+4周足月剖宫产出一男活婴，胎儿出生Apgar评分满分，生后出现了与Simpson-Golabi-Behmel综合征1型相符的症状及体征，转入新生儿科得到及时救治。
截至2022年，产前WES从超声结构异常胎儿的多系统研究逐渐深入发展至针对某一特征的队列研究，目前已有一些对NT增厚胎儿行产前WES检测的报道（表6），主要是在CMA结果阴性的NT增厚胎儿中应用WES，其阳性诊断率为2.2%~23.5%。本研究中，WES在CMA结果正常的49例NT增厚胎儿中检出单基因遗传病5例，阳性诊断率为10.2%。虽然不同研究的纳入标准、样本量及种族差异等可使阳性诊断率相差较大，但总体来说，WES对包括CMA在内的传统产前诊断结果阴性的NT增厚胎儿具有重要作用，并可用于识别单基因变异等。然而，要将WES应用于产前临床仍面临各种挑战。本研究中，WES检测还发现2例与表型相关但遗传证据不足的致病性变异（表5），提示当胎儿表型不完整、遗传证据不足时，WES检出结果的解释仍较困难。因此，对于WES在产前诊断中的应用，仍需相关指南在产前表型不完整或致病性证据不足时给予指导。
综上所述，WES在CMA结果阴性的NT增厚胎儿中可检测到单基因遗传病，尤其是合并结构畸形的NT增厚胎儿；此外，NT值<3.5 mm者也应警惕合并单基因遗传病的可能。但是，WES在产前诊断中的应用仍面临着检测费用高、应用指南尚不完善等诸多挑战，未来仍需更大样本量的研究来为WES在产前临床应用的进一步优化提供依据。
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  • 河南省2020年科技发展计划(202102310388)
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参考文献 引证文献
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2023年第48卷第3期
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doi: 10.11855/j.issn.0577-7402.2023.03.0311
  • 接收时间：2022-06-17
  • 首发时间：2025-12-03
  • 出版时间：2023-03-28
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  • 收稿日期：2022-06-17
  • 录用日期：2022-09-21
基金
Science and Technology Development Projects of Henan(202102310388)
河南省2020年科技发展计划(202102310388)
作者信息
    河南省妇产疾病（围产医学）临床医学研究中心/郑州大学第三附属医院产前诊断中心，河南郑州 450052

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