Clinical application value of Trio-WES in prenatal diagnosis of fetuses with increased nuchal translucency
-
摘要:
目的 评估家系全外显子组测序(Trio-WES)对NT增厚胎儿产前遗传学诊断的临床效能及应用意义。 方法 选取2023年8月-2025年3月于安徽医科大学第一附属医院就诊的50例NT增厚单胎妊娠孕妇, 所有病例均同步接受羊水染色体核型、染色体微阵列分析(CMA)及Trio-WES检测, 对上述检测结果进行回顾性比较与分析。 结果 在50例NT增厚胎儿中, 遗传学检测结果显示34例(68.0%)正常, 16例(32.0%)存在异常。其中, 染色体核型检出异常5例(10.0%); CMA检出异常10例(20.0%); Trio-WES共检出异常16例(32.0%), 包括5例染色体数目异常(与染色体核型及CMA一致)、4例拷贝数变异(与CMA一致)以及7例单基因致病性变异(额外检出率为14.0%)。染色体核型与CMA的阳性率差异无统计学意义(P=0.074);Trio-WES的阳性率显著高于染色体核型(P < 0.001);而CMA与Trio-WES的阳性率差异无统计学意义(P>0.017)。在NT增厚合并高龄妊娠(孕妇年龄≥35岁)的病例中, Trio-WES异常检出率显著升高(P=0.014)。 结论 Trio-WES可显著提升NT增厚胎儿的遗传学诊断效能, 对单基因病具有独特诊断价值, 尤其在高龄妊娠群体中应用意义显著。 Abstract:Objective To evaluate the clinical efficacy and application value of trio whole-exome sequencing (Trio-WES) in the prenatal genetic diagnosis of fetuses with increased nuchal translucency (NT). Methods A total of 50 singleton pregnancies with increased NT were enrolled from the First Affiliated Hospital of Anhui Medical University between August 2023 and March 2025.All cases underwent concurrent amniotic fluid karyotyping, chromosomal microarray analysis (CMA), and trio-WES.A retrospective comparative analysis of the results was performed. Results Genetic testing identified 16(32.0%) abnormal cases and 34(68.0%) normal cases among the 50 fetuses.Specifically, the detection rates were 10.0%(5/50) by karyotyping, 20.0%(10/50) by CMA, and 32.0%(16/50) by Trio-WES.Trio-WES findings included 5 chromosomal aneuploidies (consistent with karyotyping and CMA), 4 copy number variations (consistent with CMA), and 7 pathogenic single-gene variants, yielding an incremental diagnostic yield of 14.0%.No statistically significant difference was observed between karyotyping and CMA (P=0.074).Trio-WES demonstrated a significantly higher detection rate than karyotyping (P < 0.001), while its difference compared to CMA was not statistically significant (P>0.017).In cases with both increased NT and advanced maternal age (≥35 years), the detection rate of Trio-WES was significantly higher (P=0.014). Conclusion Trio-WES significantly improves the genetic diagnostic yield for fetuses with increased NT.Its ability to identify single-gene disorders provides unique diagnostic value, demonstrating particular clinical significance in the advanced maternal age population. -
表 1 16例NT增厚胎儿遗传学检测异常结果汇总
Table 1. Summary of genetic abnormalities in 16 fetuses with thickened NT
序号 年龄
(岁)NT值
(mm)核型结果 CMA结果 CMA致
病性评级Trio-WES结果 WES致
病性评级1 36 3.6 47, XN, +18 arr(18)×3 致病 seq(18)×3 致病 2 36 3.7 47, XN, +21 arr(21)×3 致病 seq(21)×3 致病 3 28 3.9~4.2 47, XN, +21 arr(21)×3 致病 seq(21)×3 致病 4 27 4.2 47, XN, +21 arr(21)×3 致病 seq(21)×3 致病 5 35 2.8 47, XN, +21 arr(21)×3 致病 seq(21)×3 致病 6 23 2.8~3.1 46, XN arr[GRCh37]22q11.22q11.23
(22, 997, 929_23, 650, 874)x1意义不明 seq[GRCh37]del(22)(q11.22q11.23)
chr22:g.22989227_23657714del意义不明 7 31 4.3 46, XN arr[GRCh37]17q22
(55501204_56476808)x1可能致病 seq[GRCh37]del(17)(q22q22)
chr17:g.55509901_56448393del可能致病 8 35 5.0 46, XN arr[GRCh37]9p24.3p22.2
(208, 455_17, 792, 136)x1致病 seq[GRCh37]del(9)(p24.3p22.2)
chr9:g.134943_17789557del致病 9 32 4.3 46, XN arr[GRCh37]18p11.32p11.21
(136, 228_15, 099, 116)x1致病 seq[GRCh37]del (18)(p11.32p11.21)
chr18:g.47340_14853917del致病 10 30 2.8~3.2 46, XN arr[GRCh37](1-22)x2, (XN)x1 / PTEN基因c.492+2T>C杂合变异 可能致病 11 32 2.6 46, XN arr[GRCh37](1-22)x2, (XN)x1 / LDLR基因exon1-2del杂合变异 可能致病 12 24 4.3~4.5 46, XN arr[GRCh37](1-22)x2, (XN)x1 / DPYS基因c.1393C>T
DPYS基因c.48C>G复合杂合变异致病
可能致病13 36 4.1 46, XN arr[GRCh37]12p11.23p11.22
(26, 661, 888_28, 097, 149)x1意义不明 ARID2基因c.2516del杂合变异 可能致病 14 36 2.9 46, XN arr[GRCh37](1-22)x2, (XN)x1 / LZTR1基因c.742G>A杂合变异 可能致病 15 37 4.8 46, XN arr[GRCh37](1-22)x2, (XN)x1 / LDLR基因c.1747C>T杂合变异 致病 16 35 9.3 46, XN arr[GRCh37](1-22)x2, (XN)x1 / SHOC2基因c.4A>G杂合变异 致病 注：“ /”代表检测结果正常无致病性评级。 
下载: 导出CSV
表 2 Trio-WES额外检出的7例单基因变异信息
Table 2. Information on an additional 7 cases of single-gene variants detected by Trio-WES
序号 NT值(mm) 基因变异位点 致病性评级 变异来源 相关疾病 1 2.8~3.2 PTEN基因c.492+2T>C杂合变异 可能致病(PVS1+PM2_P) 父源 Cowden综合征1型 2 2.6 LDLR基因exon1-2del杂合变异 可能致病(PVS1+PM2_P) 母源 家族性高胆固醇血症1型 3 4.3~4.5 DPYS基因c.1393C>T杂合变异
DPYS基因c.48C>G杂合变异致病(PVS1+PS3+PM2_P+PM3_P)
可能致病(PS3+PM2_P+PM3)父源
母源二氢尿嘧啶酶缺陷症 4 4.1 ARID2基因c.2516del杂合变异 可能致病(PVS1+PM2_P) 母源 Cofn-Siris综合征6型 5 2.9 LZTR1基因c.742G>A杂合变异 可能致病
(PS2+PS3_P+PS4_M+PM2_P+PP3)新生
变异Noonan综合征2型 6 4.8 LDLR基因c.1747C>T杂合变异 致病(PS4+PP1_S+PP3) 父源 家族性高胆固醇血症1型 7 9.3 SHOC2基因c.4A>G杂合变异 致病(PS2_VS+PS4+PM2_P) 新生
变异Noonan综合征样病伴生长期
毛发松动症1型
下载: 导出CSV
表 3 3种检测方法阳性率比较[例(%)]
Table 3. Comparison of positive rates of the three detection methods[cases(%)]
检测方法 阳性 阴性 染色体核型 5(10.0) 45(90.0) CMA 10(20.0) 40(80.0) Trio-WES 16(32.0)a 34(68.0) χ2值 9.091 P值 < 0.001 注：与染色体核型比较，aP < 0.017。
下载: 导出CSV
-
[1] 付华钰, 苏家荪, 黄婧, 等. 胎儿颈项透明层在2.5~2.9 mm时进行产前诊断的必要性研究[J]. 中华全科医学, 2025, 23(6): 972-976. doi: 10.16766/j.cnki.issn.1674-4152.004045FU H Y, SU J S, HUANG J, et al. Study on the necessity of prenatal diagnosis when fetal nuchal translucency is between 2.5 and 2.9 mm[J]. Chinese Journal of General Practice, 2025, 23(6): 972-976. doi: 10.16766/j.cnki.issn.1674-4152.004045 [2] 佟玉龙, 李昶, 于丽, 等. 胎儿颈项透明层增厚在产前诊断中的临床意义和预后分析[J]. 中国生育健康杂志, 2023, 34(5): 476-478, 497.TONG Y L, LI C, YU L, et al. Clinical significance and prognosis analysis of increased fetal nuchal translucency in prenatal diagnosis[J]. Chinese Journal of Reproductive Health, 2023, 34(5): 476-478, 497. [3] 闫冰, 陈萍, 曹云云, 等. 单脐动脉及合并畸形的产前超声分析[J]. 诊断学理论与实践, 2023, 22(1): 31-36.YAN B, CHEN P, CAO Y Y, et al. Prenatal ultrasound analysis of single umbilical artery and combined malformations[J]. Journal of Diagnostics Concepts & Practice, 2023, 22(1): 31-36. [4] 李荣, 林晓莹, 吴晓昀, 等. 超声结合WES对Treacher Collins综合征胎儿的产前诊断[J]. 中国产前诊断杂志(电子版), 2022, 14(1): 45-49.LI R, LIN X Y, WU X Y, et al. Prenatal diagnosis of a fetal with Treacher Collins syndrome by ultrasound and WES[J]. Chinese Journal of Prenatal Diagnosis(Electronic Version), 2022, 14(1): 45-49. [5] 廖灿. 染色体微阵列技术及全外显子测序在先心病产前诊断中的应用价值[J]. 中国产前诊断杂志(电子版), 2023, 15(1): 6-12.LIAO C. The application value of chromosomal microarray analysis and whole exome sequencing in prenatal diagnosis of congenital heart disease[J]. Chinese Journal of Prenatal Diagnosis(Electronic Version), 2023, 15(1): 6-12. [6] 李萌, 蒙达华, 付华钰, 等. 199例妊娠中晚期胎儿室间隔缺损的遗传学因素研究[J]. 中华全科医学, 2023, 21(2): 267-269. doi: 10.16766/j.cnki.issn.1674-4152.002861LI M, MENG D H, FU H Y, et al. Genetic factors of ventricular septal defect in 199 cases in the second or third trimester of pregnancy[J]. Chinese Journal of General Practice, 2023, 21(2): 267-269. doi: 10.16766/j.cnki.issn.1674-4152.002861 [7] JI X Q, LI Q M, QI Y M, et al. When NIPT meets WES, prenatal diagnosticians face the dilemma: genetic etiological analysis of 2, 328 cases of NT thickening and follow-up of pregnancy outcomes[J]. Front Genet, 2023, 14: 1227724. DOI: 10.3389/fgene.2023.1227724. [8] VO T M, HOANG N T, NGUYEN T T, et al. Chromosomal anomalies in fetuses with increased nuchal translucency: a Vietnamese retrospective study[J]. Cureus, 2024, 16(10): e72235. DOI: 10.7759/cureus.72235. [9] 邱惠国, 张彧梅. 染色体微阵列联合染色体核型分析对颈项透明层增厚胎儿的产前诊断价值[J]. 中国妇幼保健, 2024, 39(24): 4959-4963.QIU H G, ZHANG Y M. The value of chromosomal microarray analysis combined with karyotyping in prenatal diagnosis of fetuses with increased nuchal translucency[J]. Maternal and Child Health Care of China, 2024, 39(24): 4959-4963. [10] 侯磊, 李介岩, 齐科研, 等. 5例努南综合征胎儿的产前诊断家系分析[J]. 生殖医学杂志, 2024, 33(8): 1074-1079.HOU L, LI J Y, QI K Y, et al. Prenatal diagnosis and genetic analysis of 5 fetuse of Noonan syndrome[J]. Journal of Reproductive Medicine, 2024, 33(8): 1074-1079. [11] 代海兵, 鄢盛恺. 家族性高胆固醇血症的基因诊断研究进展[J]. 临床心血管病杂志, 2023, 39(5): 348-354.DAI H B, YAN S K. Research progress in genetic diagnosis of familial hypercholesterolemia[J]. Journal of Clinical Cardiology, 2023, 39(5): 348-354. [12] SCHRIER VERGANO S A. ARID2, a milder cause of Coffin-Siris syndrome? Broadening the phenotype with 17 additional individuals[J]. American J Med Genetics Pt A, 2024, 194(6): e63540. DOI: 10.1002/ajmg.a.63540. [13] KASERA B, SHINAR S, EDKE P, et al. Deep-learning computer vision can identify increased nuchal translucency in the first trimester of pregnancy[J]. Prenat Diagn, 2024, 44(5): 535-543. doi: 10.1002/pd.6559 [14] LI C Y, WANG Y, ZENG C Z, et al. Trio-whole exome sequencing reveals the importance of de novo variants in children with intellectual disability and developmental delay[J]. Sci Rep, 2024, 14(1): 27590. DOI: 10.1038/s41598-024-79431-x. [15] ZHOU Y L, LU X X, ZHANG Y H, et al. Prenatal genetic diagnosis of fetal cystic hygroma: a retrospective single-center study from China[J]. Cytogenet Genome Res, 2022, 162(7): 354-364. doi: 10.1159/000528600 [16] HUANG R B, FU F, ZHOU H, et al. Prenatal diagnosis in the fetal hyperechogenic kidneys: assessment using chromosomal microarray analysis and exome sequencing[J]. Hum Genet, 2023, 142(6): 835-847. doi: 10.1007/s00439-023-02545-1 [17] 刘建珍, 林铿, 覃燕龄, 等. 染色体微阵列技术贯序全外显子组测序在胎儿超声异常产前诊断的应用价值[J]. 中国产前诊断杂志(电子版), 2025, 17(2): 25-32.LIU J Z, LIN K, QIN Y L, et al. The application value of chromosomal microarray technology and sequential whole exome sequencing in prenatal diagnosis of fetal ultrasound abnormalities[J]. Chinese Journal of Prenatal Diagnosis(Electronic Version), 2025, 17(2): 25-32. [18] 王芳, 张秀珍, 吕建利. 高龄孕妇胎儿颈项透明层及染色体核型检测的临床意义[J]. 新乡医学院学报, 2023, 40(8): 759-764.WANG F, ZHANG X Z, LYU J L. Clinical significance of fetal nuchal translucency and chromosome karyotype testing in advanced maternal age pregnant women[J]. Journal of Xinxiang Medical University, 2023, 40(8): 759-764. [19] ZENG Z Y, ZHANG L, ZHOU Y Q, et al. Clinical utility of trio whole exome sequencing in fetuses with ultrasound anomalies[J]. Hum Genomics, 2025, 19(1): 37. DOI: 10.1186/s40246-025-00745-6. [20] GUSEVA M, SHIROKOVA N, KAPITONOVA O, et al. Application of whole-exome sequencing (WES) for prenatal determination of causes of fetal abnormalities[J]. Genes, 2025, 16(5): 547. DOI: 10.3390/genes16050547. [21] QIAN G H, YANG N Y, DENG F, et al. SNV/indel and CNV analysis in trio-WES for intellectual and developmental disabilities: diagnostic yield & cost-effectiveness[J]. Clin Genet, 2025, 107(4): 402-412. doi: 10.1111/cge.14677
点击查看大图
表(3)
计量
- 文章访问数: 7
- HTML全文浏览量: 3
- PDF下载量: 1
- 被引次数: 0
