The ongoing development of high-throughput sequencing technology and continuous decline of sequencing cost have made it possible to carry out large-scale screening for genetic diseases, which are the main component of birth defects. The screening of genetic diseases is expected to significantly reduce the rate of birth defects and the burden of genetic diseases to the affected families and the society. Taking Down syndrome as an example, through the analysis of the cost-benefit ratio of relevant screening programs, this article has summarized the socio-economic indicators to be considered during the design and development of genetic disease screening.
Cost-Benefit Analysis ; Down Syndrome/genetics* ; Genetic Testing ; Humans

OBJECTIVE: To evaluate the efficacy of non-invasive prenatal testing (NIPT) in the prenatal screening and its role in the system of prenatal diagnosis. METHODS: A total of 22 649 singleton pregnant women who were registered and finally delivered or had induced labor at Beijing Obstetrics and Gynecology Hospital of Capital Medical University were enrolled. The routes of prenatal screening were analyzed to evaluate the efficacy of prenatal screening. Meanwhile, 9268 pregnant women who underwent invasive prenatal diagnosis procedure were enrolled. The indications and results of prenatal diagnosis were analyzed to evaluate the effectiveness of prenatal screening. RESULTS: 60.24% of singleton pregnant women have opted for Down syndrome screening, and their age was mainly under 35. The proportion of women opted for NIPT was 34.74%, and were mainly between 35 and 39. The overall diagnostic rate of trisomy 21, 18 and 13 trisomy for those with high risk by NIPT was 0.89%, which yielded a positive predictive value of 75.71%. For those with moderate risk by serum screening, 0.30% was predicted with a high risk by NIPT. Among women undergoing prenatal diagnosis, 63.04% and 21.22% had the indication of advanced age or high risk by serum screening, and the positive predictive values were 5.1% and 5.13%, respectively. By contrast, 2.30% of women undergoing prenatal diagnosis had a high risk by NIPT, which yielded a positive predictive value of 54.46%. CONCLUSION With the change of the age composition of pregnant women and increase in the complexity of pregnancy in China, to build a prenatal screening system based on NIPT will be helpful to improve the efficiency of the current system of prenatal screening and diagnosis.
China ; Down Syndrome/genetics* ; Female ; Humans ; Pregnancy ; Prenatal Diagnosis ; Trisomy 13 Syndrome ; Trisomy 18 Syndrome

OBJECTIVE: To prepare a quality control sample for non-invasive prenatal screening (NIPS) and evaluate its quality and stability. METHODS: According to the biological characteristics of cell-free fetal DNA derived from the plasma of pregnant women, the simulated samples were prepared by mixing genomic DNA fragments derived from individuals with trisomy 21, trisomy 18 and trisomy 13 and background plasma. The samples were then compared with commercially made quality control products tested on various NIPS platforms and stored at -80℃, -20℃, 4℃, 24℃ and 37℃ for various periods of time. RESULTS: The simulated samples have attained the expected results and could be detected on various platforms and stored at -80℃and -20℃ for at least 30 days. CONCLUSION A simulated sample was successfully prepared and possessed good stability. It can be used as the quality control sample for NIPS.
Aneuploidy ; Down Syndrome/genetics* ; Female ; Humans ; Noninvasive Prenatal Testing ; Pregnancy ; Prenatal Diagnosis ; Trisomy/genetics*

OBJECTIVE: To analyze the clinical and molecular biological characteristics of a neonate with myeloid proliferation related to Down syndrome (DS). METHODS: The neonate, who was suspected for Down syndrome, was analyzed in terms of clinical feature, peripheral blood cell morphology, fluorescence in situ hybridization (FISH), immunological classification and other laboratory tests. On hundred and fourteen leukemia-related genes were subjected to next-generation sequencing (NGS). RESULTS: Laboratory test revealed obvious abnormal liver function and coagulation function, anemia, and extreme leukocytosis. Cell smear indicated significantly increased progenitor cells, which conformed to proliferation of megakaryocytes. FISH showed trisomy 21. By NGS, c.220+dupT, a novel mutation, was identified in exon 2 of the GATA1 gene, which encodes a N-terminal activation domain and has a frequency of 95.8%. No mutation was identified among the remaining 113 genes. CONCLUSION The neonate had DS and GATA1 gene mutation. High percentage of circulating blasts should be considered as transient myelodysplasia but not congenital leukemia.
Down Syndrome ; genetics ; GATA1 Transcription Factor ; genetics ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Mutation ; Trisomy

OBJECTIVE: To analyze the Z values of true and false positive cases by non-invasive prenatal testing (NIPT) in order to improve its accuracy in clinical practice. METHODS: Results of 24 384 NIPT tests were reviewed. For cases with high risks for trisomies 21, 18 and 13, the range of Z values in true and false positive cases was analyzed and discussed. RESULTS: A total of 335 high-risk cases were identified by NIPT, among which 256 had elected prenatal diagnosis, 153 (59.77%) were verified as true positives, and 103 (40.23%) were false positives, and the area under the curve (AUC) was 0.9994. For NIPT screening, the positive predictive value (PPV) for trisomy 21 was 100% when Z>13, regardless if the pregnant woman was over 35. When 335 and about 41.6% (5/12) for those<35. For trisomy 18, the PPV was 100% when Z>13, and only 14.3% (1/7) when 3CONCLUSION NIPT is a technique similar to prenatal diagnosis and has a high positive predictive value for trisomies 18 and 21. Proper classification and division of the high-risk Z value of NIPT can further improve the positive predictive values for trisomies 21, 18 and 13 in different intervals, and is more helpful to guide clinicians in genetic counseling for high-risk pregnant women. Meanwhile, the compliance of prenatal diagnosis in high risk NIPT pregnant women with Z value between 3~13 was improved.
Female ; Pregnancy ; Humans ; Trisomy 13 Syndrome/genetics* ; Trisomy/genetics* ; Down Syndrome/genetics* ; Chromosome Disorders/genetics* ; Trisomy 18 Syndrome/diagnosis* ; Prenatal Diagnosis/methods*

OBJECTIVE: To evaluate the feasibility of non-invasive prenatal testing (NIPT) for the screening of fetal chromosome aneuploidies in twin pregnancies. METHODS: A total of 2 745 women with twin-pregnancies were subjected for NIPT screening. Chromosomal karyotyping and chromosomal microarray analysis (CMA) were carried out on amniotic fluid samples from those with a high risk for fetal chromosome aneuploidies, and the diagnosis and pregnancy outcome were followed up. The sensitivity, specificity, positive predictive value and false positive rate of the NIPT were calculated. RESULTS: Compared with other chromosomal abnormalities, NIPT had a higher efficacy for trisomy 21 and sex chromosomal aneuploidy (SCA) in twin pregnancies (with sensitivity being 100%, 100%, and specificity being 99.93%, 99.9%, respectively). It is difficult to evaluate the efficacy for trisomies 18 and 13 due to the limited data. For chromosome microdeletions and microduplications spanning 15 ~ 21 Mb, NIPT also had a certain detection rate. Compared with women with natural conception, NIPT had a higher detection rate for those with twin pregnancies by assisted reproduction (P < 0.05). CONCLUSION It is feasible to use NIPT for the detection of chromosome aneuploidies in women with twin pregnancies.
Pregnancy ; Female ; Humans ; Pregnancy, Twin ; Prenatal Diagnosis ; Down Syndrome/genetics* ; Chromosome Aberrations ; Aneuploidy ; Trisomy 18 Syndrome/genetics* ; Trisomy

Down syndrome is caused by partial or complete triplication of genes located on chromosome 21. Its incidence increases dramatically with the age of women. Hypotheses proposed for this have included abnormal homologous recombination, defective spindle assembly, biological aging, reduction of cohesion complexes, endocrine disorders, oocyte selection model, and single nucleotide polymorphisms of genes that maintain chromosome stability, etc. A literature review is provided here.
Aging ; genetics ; Chromosomes, Human, Pair 21 ; genetics ; Down Syndrome ; genetics ; Female ; Humans ; Maternal Age ; Oocytes ; metabolism ; Polymorphism, Single Nucleotide ; genetics

OBJECTIVE: To analyze the results of prenatal diagnosis and outcome of pregnancy for women with a high risk for fetal aneuploidies. METHODS: A total of 747 cases of prenatal diagnosis by amniocentesis due to high risks by non-invasive prenatal testing (NIPT) were selected from January 2015 to March 2022 in the Drum Tower Hospital Affiliated to Nanjing University Medical School. The amniotic fluid samples were subjected to chromosomal karyotyping and/or chromosomal microarray analysis. All cases were followed up by searching the birth information or telephone calls, and the results were recorded. 2 test or F test were used for comparing the difference between the groups. RESULTS: Among the 747 pregnant women with a high risk by NIPT, 387 were true positives, and the overall positive predictive value (PPV) was 51.81%. The PPVs for trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13) and sex chromosome aneuploidies (SCA) were 80.24% (199/248), 60% (48/80), 14% (7/50) and 38.97% (106/272), respectively. The PPV for T21 was significantly higher than T18 and T13 (χ² = 85.216, P < 0.0001). The PPV for other chromosomal aneuploidies and copy number variations (CNVs) were 11.11% (5/45) and 40.74% (22/52), respectively. The PPV for increased X chromosomes was significantly higher than X chromosome decreases (64.29% vs. 22.22%, χ² = 5.530, P < 0.05). The overall PPV for elder women (≥ 35 years old) was significantly higher than younger women (69.35% vs. 42.39%, χ² = 49.440, P < 0.0001). For T21 and T18, the PPV of Z ≥ 10 group was significantly higher than that for 3 ≤ Z < 5 group or 5 ≤ Z < 10 group (P < 0.05). Among 52 cases with a high risk for CNVs, the PPV for the ≤ 5 Mb group was significantly higher than the 5 Mb < CNVs < 10 Mb or > 10 Mb groups (60% vs. 30%60% vs. 23.53%, P < 0.05). Among the 387 true positive cases, 322 had opted for induced labor, 53 had delivered with no abnormal growth and development, and 12 were lost during the follow-up. CONCLUSION The PPVs for common chromosomal aneuploidies are related to the age and Z value of the pregnant women, which were higher in the elder group and higher Z value group. In addition, the PPV is associated with high risk types. The PPV for T21 was higher than T18 and T13, and that for 45,X was lower than 47,XXX, 47,XYY or 47,XXY syndrome. NIPT therefore has relatively high PPVs for the identification of chromosomal CNVs.
Female ; Pregnancy ; Humans ; Aged ; Adult ; DNA Copy Number Variations ; Prenatal Diagnosis/methods* ; Down Syndrome/genetics* ; Aneuploidy ; Trisomy 18 Syndrome/genetics* ; Trisomy 13 Syndrome/diagnosis* ; DNA ; Trisomy/genetics*

OBJECTIVETo establish a new diagnostic method for Down's syndrome using polymerase chain reaction (PCR).

METHODSDNA extracted from five healthy individuals and five Down's syndrome patients was amplified in six specific tetranucleotide repeat loci on chromosome 21 using PCR. An accurate diagnosis was made by analyzing allelic distribution at each locus.

RESULTSAll Down's syndrome patients were identified as having at least two loci with three alleles, while none of the healthy individuals had three alleles. In addition, when two alleles were identified for a particular locus in the Down's syndrome samples, it was more likely that the intensity ratio between the two alleles was close to 2:1.

CONCLUSIONThe molecular method can provide a fast, accurate, and economical alternation for the traditional cytogenetic diagnostic method for Down's syndrome.

Cytogenetic Analysis ; methods ; Down Syndrome ; diagnosis ; genetics ; Humans ; Polymerase Chain Reaction

BACKGROUNDBrain hypoplasia and mental retardation in Down syndrome (DS) can be attributed to a severe and selective disruption of neurogenesis. Secondary disruption of the transcriptome, as well as primary gene dosage imbalance, is responsible for the phenotype. MicroRNA (miRNA) expression is relatively abundant in brain tissue. Perturbed miRNA expression might contribute to the cellular events underlying the pathology in DS.

METHODSMiRNA expression profiles in the cerebrum of Ts65Dn mice, a DS model, were examined with a real-time RT-PCR array. MiRNA target gene expression was detected by real-time quantitative PCR and Western blotting. Based on the prediction of their cerebrum-specific targets, the functions of the misregulated miRNAs were annotated by Gene Ontology (GO) enrichment analysis.

RESULTSA total of 342 miRNAs were examined. Among them, 20 miRNAs showed decreased expression in the brains of Ts65Dn mice, and some of these belonged to the same family. Two known targets of the miR-200 family, Lfng and Zeb2, were specifically selected to compare their expression in the cerebrum of Ts65Dn mice with those of euploids. However, no significant difference was found in terms of mRNA and protein expression levels of these genes. By enrichment analysis of the cerebrum-specific targets of each miRNA, we found that 15 of the differential miRNAs could significantly affect target genes that were enriched in the GO biological processes related to nervous system development.

CONCLUSIONPerturbed expression of multiple functionally cooperative miRNAs contributes to the cellular events underlying the pathogenesis of DS.

Animals ; Brain ; metabolism ; Disease Models, Animal ; Down Syndrome ; etiology ; genetics ; Gene Expression Regulation ; Mice ; MicroRNAs ; physiology