Expanding the Scope of Non-invasive Prenatal Testing to Detect Fetal Chromosomal Copy Number Variations.
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ABSTRACT:
SUBMITTER: Chen S
PROVIDER: S-EPMC8149898 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPregnancy complications could lead to maternal and fetal morbidity and mortality. Early diagnosing and managing complications have been associated with good outcomes. The placenta was an important organ for development of pregnancy complications. Thus, non-invasive prenatal testing technologies could detect genetic variations, such as aneuploidies and sub-chromosomal copy number variations, reflecting defective placenta by maternal plasma cffDNAs. Maternal cffDNAs had been proved to derive from trophoblast cells of placenta.ResultsIn order to find out the relationship between genetic variations and pregnancy complications, we reviewed NIPT results for subchromosomal copy number variations in a cohort of 3890 pregnancies without complications and 441 pregnancies with pregnancy complications including gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), preterm prelabor rupture of membranes (PPROM) and placenta implantation abnormalities (PIA). For GDMs, we identified three CNV regions containing some members of alpha- and beta-defensins, such as DEFA1, DEFA3, DEFB1. For PIHs, we found three duplication and one deletion region including Pcdhα, Pcdhβ, and Pcdhγ, known as protocadherins, which were complicated by hypertensive disorders. For PPROMs and PIAs, we identified one and two CNV regions, respectively. SFTPA2, SFTPD and SFTPA1, belonging to surfactant protein, was considered to moderated the inflammatory activation within the fetal extra-embryonic compartment, associated to duration of preterm prelabor rupture of fetal membranes, while MEF2C and TM6SF1 could be involved in trophoblast invasion and differentiation.ConclusionsOur findings gave a clue to correlation between genetic variations of maternal cell-free DNAs and pregnancy complications.
| S-EPMC6716937 | biostudies-literature
Project description:BackgroundFetal echogenic bowel (FEB) is associated with an increased risk of poor pregnant outcomes; however, karyotyping fails to detect copy number variations (CNVs) in FEB. This study aimed to evaluate the performance of chromosomal microarray analysis (CMA) for detection of FEB.MethodsThe medical records of 147 pregnant women with FEB recruited during December 2015 to December 2018 were retrospectively reviewed, and prenatal samples were collected for karyotyping and CMA. The detection of chromosomal abnormality was compared between karyotyping and CMA.ResultsKaryotyping identified eight cases with abnormal karyotypes (5.44% prevalence), including four fetuses with pathogenic aneuploidy, three with chromosome polymorphism and one with balanced chromosome translocation. CMA identified 13 abnormal CNVs (8.84% prevalence), including 4 fetuses with pathogenic aneuploidy as detected by karyotyping and 9 additional CNVs with normal karyotypes; however, CMA failed to detect chromosome polymorphism and balanced chromosome translocation. In fetuses with isolated FEB, no cases presented pathogenic findings and CMA detected two cases with variants of uncertain significance (VOUS). In cases presenting FEB along with other ultrasound abnormalities, CMA detected three cases with pathogenic CNVs and four cases with VOUS in addition to four cases with aneuploidy. There was no significant difference in the detection of abnormal CNVs between the fetuses with echogenic bowel alone and along with other ultrasound abnormalities (10% vs 8.67%, P > 0.05). Except 9 fetuses lost to the follow-up, the other 138 fetuses with echogenic bowel were successfully followed up. Pregnancy was terminated in 5 fetuses with chromosomal abnormality, 2 with pathogenic CNVs and 1 with VOUS, and other 16 with normal karyotypes and CMA findings but showing ultrasound abnormalities or multiple malformations.ConclusionIsolated FEB is associated with a good prognosis, and a satisfactory pregnant outcome is expected for fetuses with echogenic bowel that are negative for chromosomal anomalies and other severe structure abnormalities. CMA shows an important value in the genetic diagnosis of FEB. As a supplement to karyotyping, CMA may improve the accuracy of prenatal diagnosis of fetal intestinal malformations in pregnant women with FEB.
| S-EPMC8044071 | biostudies-literature
Project description:BackgroundNoninvasive prenatal testing (NIPT) has been wildly used to screen for common aneuplodies. In recent years, the test has been expanded to detect rare autosomal aneuploidies (RATs) and copy number variations (CNVs). This study was performed to investigate the performance of expanded noninvasive prenatal testing (expanded NIPT) in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RATs), and copy number variations (CNVs) and parental willingness for invasive prenatal diagnosis in a Chinese prenatal diagnosis center.MethodsA total of 24,702 pregnant women were retrospectively analyzed at the Women and Children's Hospital from January 2013 to April 2019, among which expanded NIPT had been successfully conducted in 24,702 pregnant women. The high-risk expanded NIPT results were validated by karyotype analysis and chromosomal microarray analysis. All the tested pregnant women were followed up for pregnancy outcomes.ResultsOf the 24,702 cases, successful follow-up was conducted in 98.77% (401/446) of cases with common trisomies and SCAs, 91.95% (80/87) of RAT and CNV cases, and 76.25% (18,429/24,169) of cases with low-risk screening results. The sensitivity of expanded NIPT was 100% (95% confidence interval[CI], 97.38-100%), 96.67%(95%CI, 82.78-99.92%), and 100%(95%CI, 66.37-100.00%), and the specificity was 99.92%(95%CI, 99.87-99.96%), 99.96%(95%CI, 99.91-99.98%), and 99.88% (95%CI, 99.82-99.93%) for the detection of trisomies 21, 18, and 13, respectively. Expanded NIPT detected 45,X, 47,XXX, 47,XXY, XYY syndrome, RATs, and CNVs with positive predictive values of 25.49%, 75%, 94.12%, 76.19%, 6.45%, and 50%, respectively. The women carrying fetuses with Trisomy 21/Trisomy 18/Trisomy 13 underwent invasive prenatal diagnosis and terminated their pregnancies at higher rates than those at high risk for SCAs, RATs, and CNVs.ConclusionsOur study demonstrates that the expanded NIPT detects fetal trisomies 21, 18, and 13 with high sensitivity and specificity. The accuracy of detecting SCAs, RATs, and CNVs is still relatively poor and needs to be improved. With a high-risk expanded NIPT result, the women at high risk for common trisomies are more likely to undergo invasive prenatal diagnosis procedures and terminate their pregnancies than those with unusual chromosome abnormalities.
| S-EPMC8045328 | biostudies-literature
Project description:To evaluate the performance of expanded non-invasive prenatal testing (expanded noninvasive prenatal testing, NIPT-Plus) in screening for fetal chromosomal abnormalities includes aneuploidies and copy number variations, a total of 23,116 pregnant women with a singleton pregnancy were recruited for NIPT-Plus. Screening positive results were verified by karyotype analysis and chromosomal microarray analysis after amniocentesis. A total of 264 pregnancies (1.14%) were positive results as predicted by NIPT-Plus, including 233 aneuploidies and 31 copy number variations. Following genetic counseling, 233 (88.26%) pregnant women underwent invasive prenatal diagnosis and 136 were verified as true positives, comprising 72 common trisomies (T21, T18, T13), 47 sex chromosomal abnormalities two rare autosomal aneuploidies (RATs) and 15 copy number variations The positive predictive value for common trisomies, SCAs, RATs and CNVs were 68.57%, 68.12%, 6.67% and 51.72%, respectively. Pregnant women with screen-positive results for common trisomies have higher rates of invasive prenatal diagnosis and pregnancy termination than those with positive results for SCAs, RATs, and CNVs. NIPT-Plus showed a good performance in detecting common trisomies, SCAs and also contributed to detecting pathogenic CNVs, but higher accuracy was required in the detection of RATs. In summary, this study provides a reference for the clinical application of NIPT-Plus for screening fetal chromosomal abnormalities in this region. Therefore, we suggest that NIPT-Plus could be widely used in clinical screening for fetal chromosomal abnormalities in combination with prenatal diagnosis and genetic counseling.
| S-EPMC9880269 | biostudies-literature
Project description:DNA Copy number variation (CNV) has recently gained considerable interest as a source of genetic variation that likely influences phenotypic differences. Many statistical and computational methods have been proposed and applied to detect CNVs based on data that generated by genome analysis platforms. However, most algorithms are computationally intensive with complexity at least O(n2), where n is the number of probes in the experiments. Moreover, the theoretical properties of those existing methods are not well understood. A faster and better characterized algorithm is desirable for the ultra high throughput data. In this study, we propose the Screening and Ranking algorithm (SaRa) which can detect CNVs fast and accurately with complexity down to O(n). In addition, we characterize theoretical properties and present numerical analysis for our algorithm.
| S-EPMC3779928 | biostudies-literature
Project description:Copy number variations (CNVs) at the chromosomal 1q21.1 region represent a group of hot-spot recurrent rearrangements in human genome, which have been detected in hundreds of patients with variable clinical manifestations. Yet, report of such CNVs in prenatal scenario was relatively scattered. In this study, 17 prenatal cases involving the 1q21.1 microdeletion or duplication were recruited. The clinical survey and imaging examination were performed; and genetic detection with karyotyping and CNV analysis using chromosomal microarray (CMA) or CNVseq were subsequently carried out. These cases were all positive with 1q21.1 CNV, yet presented with exceedingly various clinical and utrasonographic indications. Among them, 12 pregnancies carried 1q21.1 deletions, while the other 5 carried 1q21.1 duplications, all of which were within the previously defined breaking point (BP) regions. According to the verification results, 9 CNVs were de novo, 7 were familial, and the other 1 was not certain. We summarized the clinical information of these cases, and the size and distribution of CNVs, and attempted to analyze the association between these two aspects. The findings in our study may provide important basis for the prenatal diagnosis and genetic counseling on such conditions in the future.
| S-EPMC10241571 | biostudies-literature
Project description:BackgroundChromosomal segmental copy number variation (CNV) has been recently recognized as a very important source of genetic variability. Some CNV loci involve genes or conserved regulatory elements. Compelling evidence indicates that CNVs impact genome functions. The chicken is a very important farm animal species which has also served as a model for biological and biomedical research for hundreds of years. A map of CNVs in chickens could facilitate the identification of chromosomal regions that segregate for important agricultural and disease phenotypes.ResultsNinety six CNVs were identified in three lines of chickens (Cornish Rock broiler, Leghorn and Rhode Island Red) using whole genome tiling array. These CNVs encompass 16 Mb (1.3%) of the chicken genome. Twenty six CNVs were found in two or more animals. Whereas most small sized CNVs reside in none coding sequences, larger CNV regions involve genes (for example prolactin receptor, aldose reductase and zinc finger proteins). These results suggest that chicken CNVs potentially affect agricultural or disease related traits.ConclusionAn initial map of CNVs for the chicken has been described. Although chicken genome is approximately one third the size of a typical mammalian genome, the pattern of chicken CNVs is similar to that of mammals. The number of CNVs detected per individual was also similar to that found in dogs, mice, rats and macaques. A map of chicken CNVs provides new information on genetic variations for the understanding of important agricultural traits and disease.
| S-EPMC2996973 | biostudies-literature
Project description:Non-invasive prenatal testing (NIPT) has become a routine practice in screening for common aneuploidies of chromosomes 21, 18, and 13 and gonosomes X and Y in fetuses worldwide since 2015 and has even expanded to include smaller subchromosomal events. In fact, the fetal fraction represents only a small proportion of cell-free DNA on a predominant background of maternal DNA. Unlike fetal findings that have to be confirmed using invasive testing, it has been well documented that NIPT provides information on maternal mosaicism, occult malignancies, and hidden health conditions due to copy number variations (CNVs) with diagnostic resolution. Although large duplications or deletions associated with certain medical conditions or syndromes are usually well recognized and easy to interpret, very little is known about small, relatively common copy number variations on the order of a few hundred kilobases and their potential impact on human health. We analyzed data from 6422 NIPT patient samples with a CNV detection resolution of 200 kb for the maternal genome and identified 942 distinct CNVs; 328 occurred repeatedly. We defined them as multiple occurring variants (MOVs). We scrutinized the most common ones, compared them with frequencies in the gnomAD SVs v2.1, dbVar, and DGV population databases, and analyzed them with an emphasis on genomic content and potential association with specific phenotypes.
| S-EPMC9777446 | biostudies-literature
Project description:Copy number variation (CNV) is a very important phenomenon in tumor genomes and plays a significant role in tumor genesis. Accurate detection of CNVs has become a routine and necessary procedure for a deep investigation of tumor cells and diagnosis of tumor patients. Next-generation sequencing (NGS) technique has provided a wealth of data for the detection of CNVs at base-pair resolution. However, such task is usually influenced by a number of factors, including GC-content bias, sequencing errors, and correlations among adjacent positions within CNVs. Although many existing methods have dealt with some of these artifacts by designing their own strategies, there is still a lack of comprehensive consideration of all the factors. In this paper, we propose a new method, MFCNV, for an accurate detection of CNVs from NGS data. Compared with existing methods, the characteristics of the proposed method include the following: (1) it makes a full consideration of the intrinsic correlations among adjacent positions in the genome to be analyzed, (2) it calculates read depth, GC-content bias, base quality, and correlation value for each genome bin and combines them as multiple features for the evaluation of genome bins, and (3) it addresses the joint effect among the factors via training a neural network algorithm for the prediction of CNVs. We test the performance of the MFCNV method by using simulation and real sequencing data and make comparisons with several peer methods. The results demonstrate that our method is superior to other methods in terms of sensitivity, precision, and F1-score and can detect many CNVs that other methods have not discovered. MFCNV is expected to be a complementary tool in the analysis of mutations in tumor genomes and can be extended to be applied to the analysis of single-cell sequencing data.
| S-EPMC7243272 | biostudies-literature
Project description: Not available
| S-EPMC4834967 | biostudies-literature