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中国近10年婴儿染色体异常的发病率，包括那些因筛查被发现而流产的患儿。
根据现有中国近十几年的多项医学追踪研究，婴儿（含胎儿期）染色体异常的发病率并不是一个单一的固定数字，而是呈现出极大的“人群差异”：对于普通的年轻孕妇，胎儿染色体异常的发生率非常低，大约只有0.36%；但是，随着孕妇年龄的增加，或者胎儿在发育过程中出现了某些结构问题，这个发病率会急剧飙升，最高可达3.01%甚至在先天性心脏病胎儿中高达24.5%。更令人震惊的是，在早期自然流产的胚胎中，有高达58.64%是因为染色体异常导致的。也就是说，很多染色体异常的患儿，在被筛查出来之前，就已经被大自然“优胜劣汰”了。
为了让您轻松看懂这些庞大的医学数据，我们先来打个简单的比方。您可以把“染色体”想象成是一本厚厚的《人体制造说明书》。这本说明书必须不多不少、一字不差，宝宝才能健康发育。如果这本说明书多印了一卷、少印了一册（医学上叫作“非整倍体”，比如多了一条21号染色体导致的唐氏综合征），或者某一页被撕掉了一角、多粘了一段（医学上叫作“微缺失”或“微重复”，也就是拷贝数变异/CNV），这就叫作“染色体异常”。
接下来，我们将结合近十几年来中国各地的大型医学研究，为您详细拆解这本“说明书”出错的概率到底有多大。
一、 妈妈的年龄：决定“说明书”印刷质量的关键
母亲的怀孕年龄，是目前医学界公认的与胎儿染色体异常最直接相关的因素。随着年龄的增长，卵子这台“复印机”老化，在复制生命说明书时出错的概率就会成倍增加。
2016年，北京妇产医院进行了一项涵盖9000多名产妇的庞大研究。数据清晰地揭示了年龄的威力：
- 35岁以下的年轻妈妈：胎儿出现染色体异常的概率仅为0.36%。
- 35岁到39岁的妈妈：异常概率升高到了1.23%。
- 40岁及以上的高龄妈妈：异常概率直接飙升到了3.01%。
同时，另一项覆盖了全国多家医院、针对46258名35岁以上高龄孕妇的长达十年的追踪研究也显示，高龄孕妇群体中，存在严重胎儿染色体异常的总体发生率为1.53%。在这些异常中，最常见的就是大家熟知的“唐氏综合征”（也就是21三体综合征，宝宝多了一条21号染色体，会导致智力低下和发育迟缓），占了所有严重异常的55.9%，其单独的发病率达到了0.86%。研究明确指出，一旦孕妇年龄达到或超过39岁，宝宝患上唐氏综合征等严重染色体疾病的风险会显著增加。
二、 大自然的“质检员”：自然流产中的惊人数据
您在问题中提到了“包括那些因筛查被发现而流产的患儿”。事实上，除了人工干预的流产，大自然本身就自带一个非常严格的“质检系统”。很多染色体严重异常的胚胎，在妈妈还没来得及做产检时，就已经悄悄停止了发育。
广州市妇女儿童医疗中心曾对1983例自然流产的病例进行了回顾性分析。医生们提取了流产出来的绒毛组织（绒毛就像是胚胎扎在妈妈子宫里的“树根”，它的遗传物质和宝宝是一样的）进行检测。结果非常惊人：在成功检测的样本中，高达58.64%（1038例）的流产是因为胚胎的染色体存在异常。
在这个数据背后，隐藏着一个略带残酷但又极其科学的自然规律——胚胎染色体异常是导致早期自然流产最常见的原因。大自然通过这种方式，提前终止了那些有着严重基因缺陷生命的孕育过程。研究还发现，随着妈妈年龄的增加，流产物中染色体异常的比例还会进一步上升：35岁及以上的高龄组中，这一比例高达68.38%，明显高于年轻组的56.24%。
三、 产检的“放大镜”：当胎儿出现异常表现时
如果在早期大自然的“质检”中幸存下来，接下来宝宝还要面对现代医学的“雷达”——各种产前超声检查（也就是我们常说的B超）。如果B超大夫在屏幕上看到了某些不对劲的地方，那么宝宝染色体异常的概率就会大大增加。
1. 超声软指标异常（大夫眼里的“可疑线索”） 有时候大夫在B超里没有看到明显的器官缺损，但会看到一些“软指标”（比如胎儿颈部透明层增厚、鼻骨缺失或发育不良等）。这就像是警察办案时发现的可疑脚印。湖南湘雅医院等机构对15263名胎儿的基因组测序显示，带有这些超声软指标的胎儿，查出严重染色体异常（包括多或少了一条染色体，以及关键基因片段丢失）的概率在3.04%到3.40%左右。特别是“鼻骨缺失或发育不良”这个线索，它预示着染色体数量不对的风险高达5.22%。
2. 先天性心脏病（宝宝的心脏没长好） 先天性心脏病是胎儿期最常见的出生缺陷之一。常州妇幼保健院对200名患有先天性心脏病的胎儿进行了深度基因检测（使用了CMA技术，您可以把它理解为一种高级的基因显微镜，能看到染色体上微小的缺失）。结果发现，高达24.5%的先心病胎儿存在染色体异常。如果胎儿不仅心脏有问题，还合并了身体其他部位的畸形（医学上叫非孤立性先心病），染色体异常的比例更是高达31.8%。面对这样的诊断，许多家庭最终做出了艰难的选择。在福建的一项涉及1492名先心病胎儿的研究中，如果胎儿心脏有问题且伴随其他器官畸形，终止妊娠（即引产）的比例高达81.24%。
3. 胎儿骨骼发育不良（四肢短小等骨骼问题） 当胎儿在妈妈肚子里出现骨骼发育不正常的迹象时，基因缺陷往往是背后的罪魁祸首。一项针对147名超声提示骨骼发育不良胎儿的研究显示，染色体异常的检出率达到了15.6%。如果骨骼问题还伴随着其他系统的异常，这个检出率会飙升到28.6%。
4. 胎儿水肿（宝宝全身异常积水） 非免疫性胎儿水肿是一种非常凶险的胎儿异常。南方地区的一项涵盖482例胎儿水肿的研究发现，除了最常见的地中海贫血（占61.8%）外，染色体异常是第二大诱因，占了13.5%。在另一项广州的独立研究中，给这类水肿胎儿做全面的基因检测，发现24.8%的宝宝携带有临床意义的严重基因或染色体异常，而这些确诊异常的宝宝中，高达92.6%最终面临了终止妊娠的结局。
四、 曾经受过伤的妈妈：不良孕产史的预警
有些妈妈非常不容易，她们之前可能经历过反复的胎停育、死胎或者生过有缺陷的孩子，这在医学上被称为“不良孕产史”。
浙江金华的一项研究专门针对这部分孕妇进行了产前羊水穿刺诊断（用一根细针从孕妇肚子里抽一点羊水，提取宝宝脱落的细胞来查基因）。在94名有不良孕产史的孕妇中，查出胎儿染色体异常的比例达到了11.7%。这说明，如果过去有不好的生育经历，下一次怀孕时宝宝染色体异常的风险依然处于一个较高的水平。
总结
综合来看，如果您只是想知道普通人群中“健康夫妻怀上染色体异常宝宝”的概率，这个数字是让人安心的（不到千分之四）。
但是，由于中国庞大的人口基数，以及二胎、三胎政策放开后高龄产妇数量的增加，那些“不幸中招”的绝对数量依然不可忽视。这些异常的胚胎中，有一大半在怀孕极早期就会通过自然流产的方式离开我们；而剩下的那部分，如果在产检（如唐氏筛查、无创DNA、大排畸B超）中暴露出心脏缺陷、骨骼畸形、严重水肿等问题时，其背后隐藏染色体异常的概率将高达10%到30%以上。对于这些由于筛查出严重致死、致残性染色体异常的胎儿，医学伦理和临床实践中通常会给予家庭充分的遗传咨询，很多家庭为了不让孩子出生后承受巨大的痛苦，会无奈选择终止妊娠。这也是现代医学产前诊断技术最重要的意义所在——提早发现，减少严重出生缺陷，保护家庭的未来。
References
1[Clinic characteristics of women with advanced maternal age and perinatal outcomes].PubMed
Y Chen, X L Zheng, S W Wu, et al.
Zhonghua Fu Chan Ke Za Zhi. 2017 Aug 25;52(8):508-513. doi: 10.3760/cma.j.issn.0529-567X.2017.08.002.
To explore the association between maternal age and perinatal outcomes. Totally, 3 151 women with advanced maternal age and 6 098 women younger than 35 years old who delivered in Beijing Obstetrics and Gynecology Hospital in 2016 were recruited. Their clinic characteristics and perinatal outcomes were collected to divide into 3 groups based on delivery age, Group 1 (aged 35-39 years, 2 683 cases), Group 2 (aged ≥40 years, 366 cases) and the control group (aged<35 years, 6 098 cases). The association between maternal age and adverse perinatal outcomes were analyzed, including hypertensive disorder complicating pregnancy, gestational diabetes mellitus (GDM), preterm birth and postpartum hemorrhage. The rate of cesarean section history (27.39%, 33.61%, 5.53%) or previous myomectomy history (2.80%, 5.46%, 0.72%) were compared between the advanced maternal age groups and the control group, and the differences were statistically significant (<0.05). The percentage of prepregnancy overweight and obesity (29.67%, 27.05%, 18.47%), complicated with myoma (14.83%,19.95%, 5.64%) were compared among the three groups, and the differences were statistically significant (<0.05). The percentage of pregnancy through assisted reproductive technology (9.84%, 15.03%, 3.12%) also had statistically significant differences (<0.05). The incidence of fetal chromosomal abnormalities (1.23%, 3.01%, 0.36%) and fetal malformations (1.94%, 4.37%, 0.48%) increased with the maternal age, with statistically significant differences (<0.01). The mobidity of hypertensive disorders (9.84%, 13.11%, 9.23%), pregestational diabetes mellitus (1.83%, 2.19%, 0.72%), gestational diabetes mellitus (22.70%, 28.42%, 14.87%), premature rupture of membranes (25.57%, 19.40%, 31.42%), placenta previa (2.05%, 2.46%, 0.92%), preterm birth(8.35%, 11.20%, 5.51%), postpartum hemorrhage (25.11%, 18.31%, 20.27%) and forceps delivery (5.42%, 2.33%, 5.71%) were compared, and the differences were statistically significant (<0.05). The cesarean section rate in primipara (45.42%, 75.74%, 21.33%) and multipara (51.46%, 61.54%, 30.95%) had statistically significant difference (<0.05). The proportion of macrosomia (10.80%, 8.85%, 7.96%) and neonates transferred into neonatal ICU (9.63%, 11.48%, 5.21%) in term neonates had statistically significant difference (<0.05). Women with advanced maternal age increase after new family planning policy put into effect, so do the risk of adverse perinatal outcomes. Attention and interventions should be made to cope with the occurrence of adverse perinatal outcomes.
2Association analysis between chromosomal abnormalities and fetal ultrasonographic soft markers based on 15,263 fetuses.PubMed
Lijuan Pan, Jiayu Wu, Desheng Liang, et al.
Am J Obstet Gynecol MFM. 2023 Oct;5(10):101072. doi: 10.1016/j.ajogmf.2023.101072. Epub 2023 Jun 30.
BACKGROUND: Soft markers are common prenatal ultrasonographic findings that indicate an increased risk for fetal aneuploidy. However, the association between soft markers and pathogenic or likely pathogenic copy number variations is still unclear, and clinicians lack clarity on which soft markers warrant a recommendation for invasive prenatal genetic testing of the fetus. OBJECTIVE: This study aimed to provide guidance on ordering prenatal genetic testing for fetuses with different soft markers and to elucidate the association between specific types of chromosomal abnormalities and specific ultrasonographic soft markers. STUDY DESIGN: Low-pass genome sequencing was performed for 15,263 fetuses, including 9123 with ultrasonographic soft markers and 6140 with normal ultrasonographic findings. The detection rate of pathogenic or likely pathogenic copy number variants among fetuses with various ultrasonographic soft markers were compared with that of fetuses with normal ultrasonography. The association of soft markers with aneuploidy and pathogenic or likely pathogenic copy number variants were investigated using Fisher exact tests with Bonferroni correction. RESULTS: The detection rate of aneuploidy and pathogenic or likely pathogenic copy number variants was 3.04% (277/9123) and 3.40% (310/9123), respectively, in fetuses with ultrasonographic soft markers. An absent or a hypoplastic nasal bone was the soft marker in the second trimester with the highest diagnostic rate for aneuploidy of 5.22% (83/1591) among all isolated groups. Four types of isolated ultrasonographic soft markers, namely a thickened nuchal fold, single umbilical artery, mild ventriculomegaly, and absent or hypoplastic nasal bone, had higher diagnostic rates for pathogenic or likely pathogenic copy number variants (P<.05; odds ratio, 1.69-3.31). Furthermore, this study found that the 22q11.2 deletion was associated with an aberrant right subclavian artery, whereas the 16p13.11 deletion, 10q26.13-q26.3 deletion, and 8p23.3-p23.1 deletion were associated with a thickened nuchal fold, and the 16p11.2 deletion and 17p11.2 deletion were associated with mild ventriculomegaly (P<.05). CONCLUSION: Ultrasonographic phenotype-based genetic testing should be considered in clinical consultations. Copy number variant analysis is recommended for fetuses with an isolated thickened nuchal fold, a single umbilical artery, mild ventriculomegaly, and an absent or a hypoplastic nasal bone. A comprehensive definition of genotype-phenotype correlations in aneuploidy and pathogenic or likely pathogenic copy number variants could provide better information for genetic counseling.
3Noninvasive prenatal screening in southeast China: clinical application and accuracy evaluation.PubMed
Li Wen, Jiye Gao, Leilei Huang, et al.
Expert Rev Mol Diagn. 2022 Aug;22(8):841-848. doi: 10.1080/14737159.2022.2125803. Epub 2022 Sep 22.
OBJECTIVE: To assess the clinical performance of noninvasive prenatal screening (NIPS) for both common trisomy and sex chromosome aneuploidy (SCA). METHODS: We recruited 71,888 pregnant women to undergo NIPS testing from December 2015 to June 2021. Demographic characteristics, diagnostic results, and follow-up outcomes were collected. RESULTS: There were a total of 381 high-risk cases for common trisomy and 343 positive screens for SCA. Invasive prenatal diagnosis (IPD) was performed in 507 (70.0%) participants. The positive predictive value (PPV) was 83.7% for T21, 72.5% for T18, 14.3% for T13, 31.9% for 45,X, 72.0% for 47,XXX, 89.8% for 47,XXY, and 72.2% for 47,XYY, respectively. Logistic regression analysis presented a significant association between Z-score and PPV in common trisomy (P < 0.05) while not in SCA (P > 0.05). PPV in the high-risk group (Z-score ≥ cutoff) was superior to that in the intermediate risk group (3 ≤ Z-score < cutoff) for T21/T18/T13. PPV for 45,X, 47,XXY, and 47,XYY tended to be higher with the increasing Z-score, except for 47,XXX. CONCLUSIONS: NIPS would be a valuable strategy in prenatal screening, while cautions should be kept in mind for subsequent genetic consulting about the risk of Z-score.
4[Chorionic villus cell culture and karyotype analysis in 1 983 cases of spontaneous miscarriage].PubMed
S M Yuan, C Liao, D Z Li, et al.
Zhonghua Fu Chan Ke Za Zhi. 2017 Jul 25;52(7):461-466. doi: 10.3760/cma.j.issn.0529-567X.2017.07.006.
To investigate the relationship between spontaneous miscarriage and embryonic chromosome abnormalities, and to evaluate the clinical application of karyotype analysis by chorionic villus cell culture. The chorionic villus karyotype of 1 983 cases of miscarriage from January 2010 to July 2016 in Guangzhou Women and Children's Mecical Center were analyzed retrospectively. The miscarried chorionic villi were obtained by curettage under sterilized condition. The chromosome specimens were prepared after chorionic villus cell culture. Karyotype analysis was performed by G-banding technique. In the 1 983 samples, successful karyotype analysis was performed in 1 770 cases, with the successful rate of 89.98%. Chromosomal abnormalities were found in 1 038 cases (58.64%, 1 038/1 770). Chromosomal structural abnormalities were found in 37 cases. The numeral abnormalities were more common than structural abnormalities, and most of the numeral abnormalities were aneupoidies. In turn, they were trisomy 16, 45,X, trisomy 22, trisomy 2, trisomy 21, trisomy 15. The most common structural abnormality was balanced translocation, including Robersonian translocation. Female embryoes accounted for 61.02% (1 080/1 770) miscarriages and for 57.4%(596/1 770) of chromosomal abnormalities, while male embroyes acoounted for 61.02% (1 080/1 770) , 57.4% (596/1 770) respectively. The proportion of female embryoes was higher than male embryoes. The median age of the patients was 30 years old (16-46 years old) . As the maternal age increased, the proportion chromosomal abnormalities increased. The incidence of chromosomal abnormalities in the advanced age group (≥35 years) was 68.38% (240/351) , which was significantly higher than that in the younger group (56.24%, 798/1 419; χ(2)=17.10, 0.01). Embryonic chromosomal abnormalities are the most common cause of early spontaneous miscarriage. The abnormalities centralize in some karyotypes. There is certain relationship between maternal age and the incidence of miscarriage, as well as the embryonic gender. Chorionic villus cell culture and karyotype analysis are helpful in finding the cause of miscarriage and counsel the patients.
5Nonimmune hydrops fetalis: Genetic analysis and clinical outcome.PubMed
Qiong Deng, Fang Fu, Qiuxia Yu, et al.
Prenat Diagn. 2020 Jun;40(7):803-812. doi: 10.1002/pd.5691. Epub 2020 May 3.
OBJECTIVE: To investigate the genetic causes and clinical outcomes of nonimmune hydrops fetalis (NIHF). METHODS: Cohort of cases of NIHF between July 2013 and December 2018. Initial genetic testing included quantitative fluorescence polymerase chain reaction for aneuploidies, karyotyping and chromosomal microarray analysis (CMA). In negative results, whole exome sequencing (WES) of the fetuses and parents was performed. Clinical post-natal follow-up assessments were conducted. RESULTS: One hundred and nine patients fulfilled the study inclusion criteria and were sequentially genetically assessed by karyotype, CMA and WES. Among them, 24.8% (27/109) had a clinically significant genetic abnormality: 21 (19%) had abnormal karyotypes; 3/72 had pathogenic/likely pathogenic copy number variants (additional yield = 4.2%); and 3 had single gene disorders. The pregnancy termination and live birth rates of the cases with positive genetic testing results were significantly different from those with negative results (92.6% vs 53.7% and 3.7% vs 31.7%, respectively, P < .05 for both). During clinical follow-up of the survivors, 3/23 (13.0%) children developed an additional phenotype. CONCLUSION: This study improves our understanding of the diagnostic yield of CMA and WES for NIHF. A genetic diagnosis of NIHF can help determine the fetal prognosis and recurrence risk and influence pregnancy decision-making.
6Diagnostic Accuracy and Chromosomal Microarray and Karyotype Analysis with Different Clinical Biomarkers for Prenatal Diagnosis of Fetal Genetic Diseases.PubMed
Feifei Cai, Ru Shen, Haiou Wang, et al.
Iran J Public Health. 2025 May;54(5):992-1002. doi: 10.18502/ijph.v54i5.18634.
BACKGROUND: We compared the diagnostic accuracy and application value of chromosome microarray (CMA) technique and karyotype analysis for prenatal diagnosis of fetal genetic diseases using different clinical markers. METHODS: This is a prospective clinical study involving 1587 pregnant women who underwent amniocentesis for prenatal diagnosis due to various abnormal clinical indications in China between May 2018 and Nov 2021. Both chromosome microarray and karyotype analysis were applied. Participants were categorized into six groups based on different indications for prenatal diagnosis. The detection rates of chromosome microarray and karyotype analysis were compared. The study utilized SPSS version 20 for data analysis, employing descriptive statistics for count data results and chi-square statistics for statistical associations between outcomes and predictors. RESULTS: Chromosome microarray and karyotype analysis detected more abnormal chromosomes in the group with abnormal NIPT, with positive detection rates of 59.68% and the group in other situation with positive detection rates of 39.22%. Overall, 343 chromosome abnormalities were detected among participants. Overall, 101 cases chose induced labor, 240 cases gave birth, 1 newborn died after delivery, 1 case of twin chose selective reduction, another fetus gave birth, and 1 case lost to follow-up. The detection rate of chromosome abnormality in high-risk population was more than 1/5, highlighting the importance of reducing the incidence of birth defects through interventional prenatal diagnosis. CONCLUSION: Clinically, Down's screening, NIPT and prenatal ultrasound screening can be conducted initially, followed by karyotype analysis and CMA detection for those with abnormal findings.
7[Clinical phenotype and genetic analysis of twelve children with ring chromosomes].PubMed
Hongsheng Yu, Xijiang Hu, Pingxia Xiang, et al.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Feb 10;40(2):191-194. doi: 10.3760/cma.j.cn511383-20211221-01009.
OBJECTIVE: To explore the prevalence and clinical manifestations of ring chromosomes among children featuring abnormal development. METHODS: From January 2015 to August 2021, 7574 children referred for abnormal development were selected, and their peripheral blood samples were subjected to G-banded chromosomal karyotyping analysis. RESULTS: Twelve cases of ring chromosomes were detected, which have yielded a prevalence of 0.16% and included 1 r(6), 2 r(9), 1 r(13), 1 r(14), 2 r(15), 1 r(21) and 3 r(X). The children had various clinical manifestations including growth and mental retardation, limb malformation, and congenital heart disease. For two children with r(9) and two with r(15) with similar breakpoints, one child with r(9) and one with r(15) only had growth retardation, whilst another with r(9) and another with r(15) also had peculiar facies and complex congenital heart disease. The r(X) has featured some manifestations of Turner syndrome. CONCLUSION: Ring chromosomes are among the common causes for severe growth and mental retardation in children with diverse clinical phenotypes. Clinicians should pay attention to those with developmental anomalies and use chromosomal analysis to elucidate their genetic etiology.
8Estimating the frequency of causal genetic variants in foetuses with congenital heart defects: a Chinese cohort study.PubMed
Fengying Lu, Peng Xue, Bin Zhang, et al.
Orphanet J Rare Dis. 2022 Jan 4;17(1):2. doi: 10.1186/s13023-021-02167-8.
BACKGROUND: The belief that genetics plays a major role in the pathogenesis of congenital heart defects (CHD) has grown popular among clinicians. Although some studies have focused on the genetic testing of foetuses with CHD in China, the genotype-phenotype relationship has not yet been fully established, and hotspot copy number variations (CNVs) related to CHD in the Chinese population are still unclear. This cohort study aimed to assess the prevalence of chromosomal abnormalities in Chinese foetuses with different types of CHD. RESULTS: In a cohort of 200 foetuses, chromosomal abnormalities were detected in 49 (24.5%) after a prenatal chromosome microarray analysis (CMA), including 23 foetuses (11.5%) with aneuploidies and 26 (13.0%) with clinically significant CNVs. The additional diagnostic yield following whole exome sequencing (WES) was 11.5% (6/52). The incidence of total chromosomal abnormality in the non-isolated CHD group (31.8%) was higher than that in the isolated CHD group (20.9%), mainly because the incidence of aneuploidy was significantly increased when CHD was combined with extracardiac structural abnormalities or soft markers. The chromosomal abnormality rate of the complex CHD group was higher than that of the simple CHD group; however, the difference was not statistically significant (31.8% vs. 23.6%, P = 0.398). The most common CNV detected in CHD foetuses was the 22q11.2 deletion, followed by deletions of 5p15.33p15.31, deletions of 15q13.2q13.3, deletions of 11q24.2q25, deletions of 17p13.3p13.2, and duplications of 17q12. CONCLUSIONS: CMA is the recommended initial examination for cases of CHD in prenatal settings, for both simple heart defects and isolated heart defects. For cases with negative CMA results, the follow-up application of WES will offer a considerable proportion of additional detection of clinical significance.
9[Prenatal diagnosis of women with an adverse reproductive history using both traditional karyotyping and SNP-array].PubMed
H S Yu, H Guo, S S Shen, et al.
Zhonghua Fu Chan Ke Za Zhi. 2018 Mar 25;53(3):155-159. doi: 10.3760/cma.j.issn.0529-567X.2018.03.003.
To explore the occurrence of fetal chromosomal abnormalities among pregnant women with an adverse reproductive history using traditional karyotyping and single nucleotide polymorphism microarray (SNP-array) technology. Totally 94 in 2 163 (4.35%) cases of singleton pregnant women with an adverse reproductive history were performed amniocentesis in Jinhua Maternal and Child Health Care Hospital from June 2015 to June 2017. Traditional karyotyping and SNP-array were employed simultaneously for prenatal diagnosis, and the detection rates of the two methods were compared. All of the 94 specimens were successfully analyzed, 11 cases were found with chromosomal anomaly, the overall detection rate was 11.7%(11/94). Seven (7.4%,7/94) abnormalities cases were detected by karyotyping, and 7(7.4%) by SNP-array. The karyotyping results of trisomy 21, and 45,X and the deletion of chromosome 13 were consistent with SNP-array. Only 3 (3.2%, 3/94) microdeletion/duplications (the sizes of duplications and deletions were between 422.4-1 708.4 kb) and 1 (1/4) loss of heterozygosity were detected by SNP-array, but were missed by karyotyping. Furthermore, 2 cases' copy number variation were found pathogenic gene related, while the other 2 were considered benign or variant of uncertain significance. Four cases (4/7) of abnormalities were detected by karyotyping, while confirmed balanced translocation and inversion by SNP-array. All patients were informed and chosen to continue the pregnancy. The rate of abnormal fetal chromosomes in pregnant women with an adverse reproductive history is still high. SNP-array is a new molecular genetic technique, and combined with use of traditional karyotyping, it could improve the detection rate of fetal chromosomal abnormalities and reduce abortion rate, thus providing a basis for genetic counseling and prenatal diagnosis.
10Prenatal diagnosis and pregnancy outcomes of 1492 fetuses with congenital heart disease: role of multidisciplinary-joint consultation in prenatal diagnosis.PubMed
Xiuqing Qiu, Zongjie Weng, Min Liu, et al.
Sci Rep. 2020 May 5;10(1):7564. doi: 10.1038/s41598-020-64591-3.
Early diagnosis of congenital heart disease (CHD) can improve the prognosis of neonates with CHD. We retrospectively evaluated the value of prenatal diagnosis of CHD by comparing the pregnancy outcomes. Prenatal diagnosis of CHD was established by echocardiographic evaluation of fetal heart. Amniotic fluid and/or cord blood genetic examination, pathological anatomy, casting specimen, and/or multidisciplinary-joint consultation (MDJC) were performed. A total of 1492 fetuses with CHD were diagnosed by prenatal echocardiography from 67834 pregnant women. There were 445, 236, 583, and 228 cases in groups A (simple CHD), B (simple CHD plus extra-cardiac abnormality), C (complex CHD), and D (complex CHD plus extra-cardiac abnormality), respectively. The pregnancy continuation rate in the four groups was 98.67%, 85.71%, 67.65%, and 36.84%, respectively (P < 0.001). The pregnancy termination rate for fetal CHD with extra-cardiac abnormalities was significantly higher than that for fetuses with only CHD (81.24% vs. 53.6%, P < 0.05). Prenatal genetic test revealed chromosomal abnormalities in 20.43% of fetuses with CHD. MDJC significantly decreased the pregnancy termination rate. In 88 cases, the original decision to terminate the pregnancy was changed after consultation and the pregnancy was continued. Of these, 87 cases culminated in live births; 65 of these children had better prognosis. Nine-segment sequential segment analysis method for prenatal fetal echocardiography was compared with the results of pathological anatomy, cast specimen, postoperative diagnosis, and postnatal ultrasound. The accuracy of prenatal ultrasound for diagnosis of fetal complex CHD and fetal simple CHD was 90.5-91.66% and 98.6%, respectively. Prenatal ultrasound is still the most effective method for fetal CHD diagnosis.
11Prenatal prevalence and postnatal manifestations of 16p11.2 deletions: A new insights into neurodevelopmental disorders based on clinical investigations combined with multi-omics analysis.PubMed
Lan Liu, Jiamin Wang, Xijing Liu, et al.
Clin Chim Acta. 2024 Jan 1;552:117671. doi: 10.1016/j.cca.2023.117671. Epub 2023 Nov 19.
BACKGROUND: The 16p11.2 deletion is one of the most common genetic aetiologies of neurodevelopmental disorders (NDDs). The prenatal phenotype of 16p11.2 deletion and the potential mechanism associated with postnatal clinical manifestations were largely unknow. We revealed the developmental trajectories of 16p11.2 deletion from the prenatal to postnatal periods and to identify key signaling pathways and candidate genes contributing to neurodevelopmental abnormalities. METHODS: In this 5-y retrospective cohort study, women with singleton pregnancies who underwent amniocentesis for chromosomal abnormalities were included. Test of copy-number variations (CNVs) involved single nucleotide polymorphism-array and CNV-seq was performed to detected 16p11.2 deletion. For infants born carrying the 16p11.2 deletion, neurological and intellectual evaluations using the Chinese version of the Gesell Development Scale. For patients observed to have vertebral malformations, Sanger sequencing for T-C-A haplotype of TBX6 was performed. For those infants with clinical manifestations, whole-exome sequencing was consecutively performed in trios to rule out single-gene diseases, and transcriptomics combined with untargeted metabolomics were performed. RESULTS: The prevalence of 16p11.2 deletion was 0.063% (55/86,035) in the prenatal period. Up to 80% (20/25) of the 16p11.2 deletions were proven de novo by parental confirmation. Approximately half of 16p11.2 deletions (28/55) were detected with prenatal abnormal ultrasound findings. Vertebral malformations were identified as the most distinctive structural malformations and were enriched in fetuses with 16p11.2 deletions compared with controls (90.9‰ [5/55] vs. 8.4‰ [72/85,980]; P < 0.001). All 5 fetuses with vertebral malformations were confirmed to have the TBX6 haplotype of T-C-A. Overall, 47.6% (10/21) infants birthed were diagnosed with NDDs of different degrees. Language impairment was the predominant manifestation (7/10; 70.0%), followed by motor delay (5/10; 50%). Multi-omics analysis indicated that MAPK3 was the central hub of the differentially expressed gene (DEG) network. We firstly reported that histidine-associated metabolism may be the core metabolic pathway related to the 16p11.2 deletion. CONCLUSION: We demonstrated the prenatal presentation, incomplete penetrance and variable expressivity of the 16p11.2 deletion. We identified vertebral malformations were the most distinctive prenatal phenotypes, and language impairment was the predominant postnatal manifestation. Most of the 16p11.2 deletion was de novo. Meanwhile, we suggested that MAPK3 and histidine-associated metabolism may contribute to neurodevelopmental abnormalities of 16p11.2 deletion.
12Genetic analysis of pregnancy loss and fetal structural anomalies by whole exome sequencing.PubMed
Jingjing Xiang, Yang Ding, Hui Tang, et al.
Orphanet J Rare Dis. 2024 Sep 9;19(1):330. doi: 10.1186/s13023-024-03340-5.
BACKGROUND: Whole exome sequencing (WES) has been recommended to investigate the genetic cause of fetal structural anomalies. In this retrospective study, we aimed to evaluate the diagnostic yield of WES in our cohort of families with pregnancy loss or termination of pregnancy due to structural anomalies. METHODS: As aneuploidy, triploidy and copy number variations (CNVs) could be detected by exome-based CNV analysis, only WES is performed in this study. And the results of 375 cases assessed by WES were analyzed. RESULTS: The overall detection rate was 32.3% (121/375), including aneuploidy and triploidy (7.5%, 28/375), CNVs (5.1%, 19/375) and single-nucleotide variants (SNVs) /insertions or deletions (Indels) (19.7%, 74/375). Among these, the diagnostic yield for likely pathogenic (LP) or pathogenic (P) CNVs is 4.8% (18/375), and the diagnostic yield for LP or P SNVs/Indels is 15.2% (57/375). And an additional 4.8% (18/375) of cases had CNVs or SNVs/Indels classified as variants of uncertain significance (VUS) with potential clinical significance. CONCLUSIONS: Our findings expand the known mutation spectrum of genetic variants related to fetal abnormalities, increase our understanding of prenatal phenotypes, and enable more accurate counseling of recurrence risk for future pregnancies.
13Performance of noninvasive prenatal testing for twin pregnancies in South China.PubMed
Dongmei Wang, Haishan Peng, Yixia Wang, et al.
J Assist Reprod Genet. 2023 Sep;40(9):2219-2231. doi: 10.1007/s10815-023-02881-1. Epub 2023 Jul 22.
OBJECTIVE: The purpose of this study was to evaluate the performance of noninvasive prenatal testing (NIPT) for the detection of chromosomal aneuploidies and copy number variations (CNVs) in twin pregnancies. METHOD: A cohort of 2010 women with twin pregnancies was recruited. 1331 patients opted for NIPT, and 679 patients opted for expanded NIPT (NIPT-plus). All high-risk patients were advised to undergo invasive prenatal diagnosis. All participants were followed up until 6 months after birth. RESULTS: Twenty-two cases were predicted to have a high risk of chromosome abnormalities by NIPT, of which 14 pregnant women underwent invasive prenatal diagnosis. The 14 cases included 3 cases of trisomy 21, 1 case of trisomy 18, 1 case of trisomy 7, 2 cases of sex chromosome aneuploidies (SCAs), and 7 cases of CNVs, of which the confirmed cases numbered 2, 1, 0, 1, and 0, respectively. Twenty cases were predicted to have a high risk of chromosome abnormalities by NIPT-plus, of which 16 pregnant women underwent invasive prenatal diagnosis. The 16 cases included 1 case of trisomy 21, 1 case of trisomy 7, 7 cases of SCAs, and 7 cases of CNVs, of which were confirmed in 1, 0, 3, and 2, respectively. No false-negative result was reported during the follow-up period. CONCLUSION: The NIPT/NIPT-plus has excellent performance in the detection of chromosome aneuploidies in twin pregnancies. But for CNVs, the effectiveness of NIPT is poor, and the NIPT-plus have a certain detection efficiency. It is worth noting that pre- and post-genetic counseling is especially important, and the chorionicity, mode of conception, clinical indications, and fetal fraction should be considered as influencing factors.
14Adverse Perinatal and Early Life Outcomes following 15q11.2 CNV Diagnosis.PubMed
Fu-Chieh Chu, Steven W Shaw, Chien-Hong Lee, et al.
Genes (Basel). 2021 Sep 23;12(10):1480. doi: 10.3390/genes12101480.
The copy number variation (CNV) of 15q11.2, an emerging and common condition observed during prenatal counseling, is encompassed by four highly conserved and non-imprinted genes-, , , and -which are reportedly related to developmental delays or general behavioral problems. We retrospectively analyzed 1337 samples from genetic amniocentesis for fetal CNV using microarray-based comparative genomic hybridization analysis between January 2014 and December 2019. 15q11.2 CNV showed a prevalence of 1.5% (21/1337). Separately, 0.7% was noted for 15q11.2 BP1-BP2 microdeletion and 0.8% for 15q11.2 microduplication. Compared to the normal array group, the 15q11.2 BP1-BP2 microdeletion group had more cases of neonatal intensive care unit transfer, an Apgar score of <7 at 1 min, and neonatal death. Additionally, the group was symptomatic with developmental delays and had more infantile deaths related to congenital heart disease (CHD). Our study makes a novel contribution to the literature by exploring the differences in the adverse perinatal outcomes and early life conditions between the 15q11.2 CNV and normal array groups. Parent-origin gender-based differences may help in the prognosis of the fetal phenotype; development levels should be followed up in the long term and echocardiography should be offered prenatally and postnatally for the prevention of a delayed diagnosis of CHD.
15Etiology and Perinatal Outcome of Nonimmune Hydrops Fetalis in Southern China.PubMed
Sheng He, Linlin Wang, Pingshan Pan, et al.
AJP Rep. 2017 Apr;7(2):e111-e115. doi: 10.1055/s-0037-1603890. Epub 2017 Jun 12.
This study aims to analyze the etiology and perinatal outcome of nonimmune hydrops fetalis (NIHF) in Southern China. All cases with NIHF diagnosed antenatally from January 1, 2007 to December 31, 2014 were identified and analyzed. Total 482 cases of NIHF were identified during the study period. The most common cause of NIHF was hemoglobin (Hb) Bart's disease (61.8%), followed by chromosomal abnormalities (13.5%), idiopathic etiology (13.1%), cardiac abnormalities (6.4%), and others (5.2%). After 20 weeks' gestation, a total of 408 cases of NIHF presented, including Hb Bart's disease (279 cases), cardiac abnormalities (27 cases), and infection (7 cases). NIHF caused by chromosomal abnormalities mainly presented between 15 and 19 weeks' gestation. Of the 482 cases, 459 cases elected termination of pregnancy. The remaining 23 cases elected to continue their pregnancy. Among them, 14 (60.9%) resulted in intrauterine fetal death, 6 had neonatal death, 3 infants survived to 1 year of age. Of the three infants, one has cerebral palsy, and the remaining two are normal. Hb Bart's disease is the most common cause of NIHF in Southern China. An effective prenatal screening and counseling program for thalassemia in this region may be the most effective way to lower the incidence NIHF.
16Sequential prenatal diagnosis of fetal skeletal dysplasia: A cohort study.PubMed
Mengting Jiang, Bin Zhang, Jing Wang, et al.
Acta Obstet Gynecol Scand. 2025 May;104(5):860-874. doi: 10.1111/aogs.15095. Epub 2025 Mar 4.
INTRODUCTION: Genetic factors are considered to be the main factors leading to fetal skeletal dysplasia (SD), and chromosomal microarray analysis (CMA) has been used clinically for the detection of SD fetuses. At present, whole exome sequencing (WES) has been applied in SD fetuses, but there is still a lack of data accumulation. The aim of this study is to perform sequential prenatal diagnosis for fetuses with SD indicated by ultrasound and to explore the clinical value of CMA followed by WES. MATERIAL AND METHODS: From January 2019 to May 2024, 147 fetuses with SD were detected by prenatal ultrasound screening. After the collection of amniotic fluid or abortive tissue, CMA was performed first, then WES was performed in the cases with a negative CMA result. RESULTS: 147 cases accepted the prenatal CMA test, and 23 cases were reported to have chromosomal abnormalities, including 9 cases of chromosomal aneuploidies, 11 cases of pathogenic copy number variants, and 3 cases of likely pathogenic copy number variants. The detection rate of chromosomal abnormalities by the prenatal CMA test was 15.6% (23/147). 58 cases with negative results of CMA underwent WES, and 21 genes with pathogenic/likely pathogenic variants were detected in 21 cases, including FGFR3, COL2A1, COL1A1, COL1A2, RUNX2, LMX1B, GLI3, SHOX, ALPL, and DYNC2H1. The rate of abnormal prenatal WES was 36.2% (21/58). In the subgroup analysis of the SD phenotype, the detection rate of chromosomal abnormalities in isolated SD fetuses was 7.7% (7/91), which was significantly lower than that in SD fetuses combined with other system abnormalities (28.6%, 16/56) (p = 0.001). The detection rate of monogenic abnormalities in short long bones with other skeletal abnormalities was 62.5% (10/16), which was higher than that in short long bones with non-skeletal abnormalities 10.5% (2/19), and the difference was statistically significant (p = 0.003). CONCLUSIONS: SD is mostly caused by monogenic abnormalities, and prenatal WES has significantly improved the detection rate of SD fetuses. The prenatal WES can be used as an important molecular genetic testing method combined with CMA in the sequential prenatal diagnosis of SD fetuses.
17A multicenter study of fetal chromosomal abnormalities in Chinese women of advanced maternal age.PubMed
Yuning Zhu, Shiming Lu, Xuming Bian, et al.
Taiwan J Obstet Gynecol. 2016 Jun;55(3):379-84. doi: 10.1016/j.tjog.2016.01.002.
OBJECTIVE: This study aimed to determine the rates of different fetal chromosomal abnormalities among women of advanced maternal age in China and to discuss the possible misdiagnosis risks of newer molecular techniques, for selection of appropriate prenatal screening and diagnostic technologies. MATERIALS AND METHODS: Second trimester amniocentesis and fetal karyotype results of 46,258 women were retrospectively reviewed. All women were ≥ 35 years old with singleton pregnancies. The rates of clinically significant chromosomal abnormalities (CSCAs), incidence of chromosomal abnormalities, and correlations with age were determined. RESULTS: From 2001 to 2010, the proportion of women of advanced maternal age undergoing prenatal diagnosis increased from 20% to 46%. The mean age was 37.4 years (range, 35-46 years). A total of 708 cases of CSCAs, with a rate of 1.53% were found. Trisomy 21 was the most common single chromosome abnormality and accounted for 55.9% of all CSCAs with an incidence of 0.86%. Trisomy 13, trisomy 18, and trisomy 21, the most common chromosome autosomal aneuploidies, accounted for 73.6% of all CSCAs, with a rate of 1.13%. As a group, the most common chromosomal aneuploidies (13/18/21/X/Y) accounted for 93.9% of all abnormalities, with a rate of 1.44%. The incidence of trisomy 21, trisomy 13/18/21 as a group, and 13/18/21/X/Y as a group was significantly greater in women aged 39 years and older (p < 0.001), but was not different between women aged 35 years, 36 years, 37 years, and 38 years. CONCLUSION: These findings may assist in genetic counseling of advanced maternal age pregnant women, and provide a basis for the selection of prenatal screening and diagnostic technologies.
18Prenatal diagnosis with chromosome microarray analysis and pregnancy outcomes of fetuses with umbilical cord cysts.PubMed
Yanping Qian, Ting Hu, Zhu Zhang, et al.
J Matern Fetal Neonatal Med. 2023 Dec;36(1):2203793. doi: 10.1080/14767058.2023.2203793.
OBJECTIVE: To investigate the prenatal diagnostic value of chromosome microarray analysis (CMA) in fetuses with isolated or non-isolated umbilical cord cysts (UCCs) of various locations and numbers. METHODS: Between November 2015 and November 2021, 45 pregnant women carrying fetuses with UCCs underwent amniocentesis and CMA. Fetal prognoses were followed from 6 months to 5 years. RESULTS: Five cases (11.1%, 5/45) of chromosomal aberrations were detected. No significant difference in total chromosome abnormalities was found between fetuses with isolated and non-isolated UCCs (13.3% [2/15] vs 10% [3/30]; > .999). No common autosomal aneuploidies were found in fetuses with isolated UCCs. At follow-up, among 45 fetuses, there were 11 (24.4%) pregnancy terminations, 26 (57.8%) live healthy births, 4 (8.9%) postnatal UCC-related surgeries, and 4 (8.9%) live births of fetuses with other diseases. The frequency of postnatal surgeries of the infants with UCCs located adjacent to the anterior abdominal wall was higher than those located adjacent to the fetal surface of the placenta (30.8% [4/13] vs 0% [0/22]; = .014). All 26 live healthy neonates and 4 neonates that underwent postnatal surgery had an overall good prognosis. CONCLUSIONS: For fetuses with isolated or non-isolated UCC, CMA could be a choice for parents after providing detailed information. Even when surgery was required, pregnancy outcomes and short- and long-term prognoses for fetuses with UCCs were favorable.
19Copy number variations of chromosome 17p11.2 region in children with development delay and in fetuses with abnormal imaging findings.PubMed
Yuanyuan Zhang, Xiaoliang Liu, Haiming Gao, et al.
BMC Med Genomics. 2021 Sep 1;14(1):215. doi: 10.1186/s12920-021-01065-z.
BACKGROUND: Deletion and duplication of the 3.7 Mb region in 17p11.2 result in two syndromes, Smith-Magenis syndrome and Potocki-Lupski syndrome, which are well-known development disorders. The purpose of this study was to determine the prevalence, genetic characteristics and clinical phenotypes of 17p11.2 deletion/duplication in Chinese children with development delay and in fetuses with potential congenital defects. METHODS: 7077 children with development delay and/or intellectual disability were screened by multiplex ligation-dependent probe amplification P245 assay. 7319 fetuses with potential congenital defects were tested using next generation sequencing technique. RESULTS: 417 of 7077 pediatric patients were determined to carry chromosome imbalance. 28 (28/7077, 0.4%) cases had imbalance at chromosome 17p11.2. Among them, 12 cases (42.9%) had heterozygous deletions and 16 cases (57.1%) had heterozygous duplications. The clinical phenotypes were variable, including neurobehavioral disorders, craniofacial/skeletal anomalies, immunologic defects, ocular problems and organ malformations. 263 of 7319 fetuses were recognized to have genomic copy number variations. Only 2 of them were found to harbor 17p11.2 imbalance. The fetus with deletion presented with ventricular septal defect and the fetus with duplication had cerebral ventricle dilation. CONCLUSION: Our study highlights the phenotypic variability associated with 17p11.2 variations in China. The results further expand the phenotypic spectrum of SMS/PTLS and increase awareness of these disruptive mutations among clinicians.
20Non-visualisation of fetal gallbladder in a Chinese cohort.PubMed
Y H Ting, P L So, K W Cheung, et al.
Hong Kong Med J. 2022 Apr;28(2):116-123. doi: 10.12809/hkmj208938. Epub 2022 Apr 20.
INTRODUCTION: Non-visualisation of fetal gallbladder (NVFGB) is associated with chromosomal abnormalities, biliary atresia, cystic fibrosis, and gallbladder agenesis in Caucasian fetuses. We investigated the outcomes of fetuses with NVFGB in a Chinese cohort. METHODS: This retrospective analysis included cases of NVFGB among Chinese pregnant women at five public fetal medicine clinics in Hong Kong from 2012 to 2019. We compared the incidences of subsequent gallbladder visualisation, chromosomal abnormalities, biliary atresia, cystic fibrosis, and gallbladder agenesis between cases of isolated NVFGB and cases of non-isolated NVFGB. RESULTS: Among 19 cases of NVFGB detected at a median gestational age of 21.3 weeks (interquartile range, 20.0-22.3 weeks), 10 (52.6%) were isolated and nine (47.4%) were non-isolated. Eleven (58.0%) cases had transient non-visualisation, four (21.0%) had gallbladder agenesis, three (15.8%) had chromosomal abnormalities (trisomy 18, trisomy 21, and 22q11.2 microduplication), one (5.2%) had biliary atresia, and none had cystic fibrosis. The incidence of serious conditions was significantly higher in the non-isolated group than in the isolated group (44.4% vs 0%; P=0.029); all three cases with chromosomal abnormalities and the only case of biliary atresia were in the non-isolated group, while all four cases with gallbladder agenesis were in the isolated group. The incidences of transient non-visualisation were similar (55.6% vs 60.0%; P=1.000). CONCLUSION: Isolated NVFGB is often transient or related to gallbladder agenesis. While investigations for chromosomal abnormalities and biliary atresia are reasonable in cases of NVFGB, testing for cystic fibrosis may be unnecessary in Chinese fetuses unless the NVFGB is associated with consistent ultrasound features, significant family history, or consanguinity.