Prenatal DNA Sequencing for Fetal Aneuploidy Also Detects Maternal Cancer: Importance of Timely Workup and Management in Pregnant Women.
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ABSTRACT:
SUBMITTER: Turriff AE
PROVIDER: S-EPMC9467676 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
Publications
Prenatal DNA Sequencing for Fetal Aneuploidy Also Detects Maternal Cancer: Importance of Timely Workup and Management in Pregnant Women.
Turriff Amy E AE Annunziata Christina M CM Bianchi Diana W DW
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20220615 22
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Project description: Not available
| S-EPMC6486016 | biostudies-literature
Project description:The aim of this study is to report the experience of noninvasive prenatal DNA testing using massively parallel sequencing in an accredited clinical laboratory.Laboratory information was examined for blood samples received for testing between February and November 2012 for chromosome 21 (Chr21), Chr18, and Chr13. Monosomy X (MX) testing was available from July 2012 for cystic hygroma indication. Outcomes were collected from providers on samples with positive results.There were 5974 samples tested, and results were issued within an average of 5.1 business days. Aneuploidy was detected in 284 (4.8%) samples (155 Chr21, 66 Chr18, 19 Chr13, 40 MX, and four double aneuploidy). Follow-ups are available for 245/284 (86%), and 77/284 (27.1%) are confirmed, including one double-aneuploidy case concordant with cytogenetics from maternal malignancy. Fourteen (0.2%) discordant (putative false-positive) results (one Chr21, six Chr18, three Chr13, three MX, and one Chr21/13) have been identified. Five (0.08%) false-negative cases are reported (two trisomy 21, two trisomy 18, and one MX). In 170 (2.8%) cases, the result for a single chromosome was indefinite.This report suggests that clinical testing of maternal cell-free DNA for fetal aneuploidy operates within performance parameters established in validation studies. Noninvasive prenatal testing is sensitive to biological contributions from placental and maternal sources.
| S-EPMC3709117 | biostudies-literature
Project description:Chromosomal aneuploidy is the major reason why couples opt for prenatal diagnosis. Current methods for definitive diagnosis rely on invasive procedures, such as chorionic villus sampling and amniocentesis, and are associated with a risk of fetal miscarriage. Fetal DNA has been found in maternal plasma but exists as a minor fraction among a high background of maternal DNA. Hence, quantitative perturbations caused by an aneuploid chromosome in the fetal genome to the overall representation of sequences from that chromosome in maternal plasma would be small. Even with highly precise single molecule counting methods such as digital PCR, a large number of DNA molecules and hence maternal plasma volume would need to be analyzed to achieve the necessary analytical precision. Here we reasoned that instead of using approaches that target specific gene loci, the use of a locus-independent method would greatly increase the number of target molecules from the aneuploid chromosome that could be analyzed within the same fixed volume of plasma. Hence, we used massively parallel genomic sequencing to quantify maternal plasma DNA sequences for the noninvasive prenatal detection of fetal trisomy 21. Twenty-eight first and second trimester maternal plasma samples were tested. All 14 trisomy 21 fetuses and 14 euploid fetuses were correctly identified. Massively parallel plasma DNA sequencing represents a new approach that is potentially applicable to all pregnancies for the noninvasive prenatal diagnosis of fetal chromosomal aneuploidies.
| S-EPMC2600580 | biostudies-literature
Project description:ObjectiveNoninvasive prenatal testing (NIPT) is widely used in clinical detection of fetal autosomal duplications or deletions. The aim of this study was to investigate the clinical application of NIPT for detection of chromosomal microdeletions.MethodsMicrodeletions of about 5 Mb in the long arm of chromosome 15 (q11.2-q12) were detected by NIPT and were confirmed by karyotype analysis and copy number variation (CNV) analysis based on high-throughput sequencing technology.ResultsThe CNV results of prenatal diagnosis showed that there were approximately 4.96 Mb of microdeletions in 15q11.2-q13.1, which was consistent with the NIPT results. The karyotype analysis showed no abnormalities.ConclusionIn this study, the microdeletion fragment of fetal chromosome 15 was successfully detected and diagnosed using NIPT. This suggests that NIPT is an efficient method to gain genetic information about chromosomal abnormalities.
| S-EPMC6642313 | biostudies-literature
Project description:Study questionCan maternal plasma cell-free DNA (cfDNA) detect chromosomal anomalies in early pregnancy loss (EPL) and recurrent pregnancy loss (RPL)?Summary answerGenome-wide cfDNA testing can serve as an alternative to cytogenetic analysis in products of conception (POCs) in RPLs and can guide further management.What is known alreadyRandom chromosomal anomalies are the single most common cause for EPL and RPL. Cytogenetic analysis in POCs may be used to direct management in RPL because the detection of random chromosomal anomalies can eliminate further unwarranted testing.Study design, size, durationThis was a prospective diagnostic test study from March 2018 to January 2019 of 109 patients experiencing pregnancy loss before 14 weeks gestation at a tertiary-care academic medical center.Participants/materials, setting, methodsBlood samples were drawn for genome-wide cfDNA testing prior to chorionic villous sampling for cytogenetic analysis of POCs with both short-term cultures (STCs) and long-term cultures (LTCs). Final analysis included 86 patients with non-mosaic cytogenetic results in POCs and available cfDNA results. Aneuploidy detection rates by cfDNA testing and POC cytogenetic analysis were compared. The first 50 samples served as the Training Set to establish pregnancy loss-specific log-likelihood ratio (LLR) thresholds using receiver-operator characteristic (ROC)-like analyses. These were then used for the entire cohort.Main results and the role of chanceSeventy-eight samples (71.5%) had results available from both STC and LTC; 12 samples (11%) had a result from STC only, and 7 samples (6.4%) had a result from LTC only. A chromosomal anomaly was detected in 55/86 (64%). The rates of chromosomal anomalies were 61, 72, 73 and 44% in patients undergoing their first, second, third and ≥4th pregnancy losses, respectively. The median cfDNA fetal fraction was 5%. With standard LLR thresholds used for noninvasive prenatal screening, the sensitivity of cfDNA in detecting aneuploidy was 55% (30/55) and with a specificity of 100% (31/31). Using pregnancy loss-specific LLR thresholds, the sensitivity of cfDNA in detecting aneuploidy was 82% (45/55), with a specificity of 90% (28/31). The positive and negative likelihood ratios were 8.46 and 0.20, respectively. Fetal sex was correctly assigned in all cases.Limitations, reasons for cautionCases with a false-positive result by cfDNA analysis would not receive the indicated RPL workup. Specificity could be improved by using a fetal fraction (FF) cutoff of 4%, but this would result in exclusion of more than a quarter of cases.Wider implications of the findingscfDNA-based testing can serve as an alternative to POC cytogenetic analysis and can guide further RPL management: if cfDNA demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended RPL workup is performed.Study funding/competing interest(s)Cell-free DNA testing was funded by Illumina, Inc., San Diego, CA. Y.Y. is a member of Illumina's Clinical Expert Panel and has received travel grants. A.B. has received travel grants from Illumina. All authors have no competing interest to declare.
| S-EPMC7259365 | biostudies-literature
Project description:Introduction Encephalomalacia in a developing fetus is a rare and devastating neurological finding on radiologic imaging. Maternal diabetic ketoacidosis (DKA) can lead to metabolic and vascular derangements which can cause fetal encephalomalacia. Case We report the case of a 27-year-old pregnant woman with White's Class C diabetes mellitus who presented in the 25th week of gestation with DKA. Four weeks after her discharge, marked fetal cerebral ventriculomegaly was noted on ultrasound. A subsequent fetal magnetic resonance imaging (MRI) demonstrated extensive, symmetric cystic encephalomalacia, primarily involving both cerebral hemispheres. The pregnancy was continued with close fetal and maternal surveillance. The patient underwent a repeat cesarean delivery in her 37th week. The infant had a 1 month neonatal intensive care unit stay with care rendered by a multiple disciplinary team of pediatric subspecialists. The postnatal course was complicated by global hypotonia, poor feeding, delayed development and ultimately required anticonvulsants for recurrent seizures. He died at the age of 9 months from aspiration during a seizure. Discussion Although the maternal mortality from DKA has declined, DKA still confers significant neurological fetal morbidity to its survivors.
| S-EPMC4239142 | biostudies-other
Project description:Current invasive procedures [amniocentesis and chorionic villus sampling (CVS)] pose a risk to mother and fetus and such diagnostic procedures are available only to high risk pregnancies limiting aneuploidy detection rate. This review seeks to highlight the necessity of investing in non invasive prenatal diagnosis (NIPD) and how NIPD would improve patient safety and detection rate as well as allowing detection earlier in pregnancy. Non invasive prenatal diagnosis can take either a proteomics approach or nucleic acid-based approach; this review focuses on the latter. Since the discovery of cell free fetal DNA (cffDNA) and fetal RNA in maternal plasma, procedures have been developed for detection for monogenic traits and for some have become well established (e.g., RHD blood group status). However, NIPD of aneuploidies remains technically challenging. This review examines currently published literature evaluating techniques and approaches that have been suggested and developed for aneuploidy detection, highlighting their advantages and limitations and areas for further research.
| S-EPMC3776677 | biostudies-literature
Project description:BackgroundCirculating cell-free (ccf) fetal DNA comprises 3-20% of all the cell-free DNA present in maternal plasma. Numerous research and clinical studies have described the analysis of ccf DNA using next generation sequencing for the detection of fetal aneuploidies with high sensitivity and specificity. We sought to extend the utility of this approach by assessing semi-automated library preparation, higher sample multiplexing during sequencing, and improved bioinformatic tools to enable a higher throughput, more efficient assay while maintaining or improving clinical performance.MethodsWhole blood (10mL) was collected from pregnant female donors and plasma separated using centrifugation. Ccf DNA was extracted using column-based methods. Libraries were prepared using an optimized semi-automated library preparation method and sequenced on an Illumina HiSeq2000 sequencer in a 12-plex format. Z-scores were calculated for affected chromosomes using a robust method after normalization and genomic segment filtering. Classification was based upon a standard normal transformed cutoff value of z = 3 for chromosome 21 and z = 3.95 for chromosomes 18 and 13.ResultsTwo parallel assay development studies using a total of more than 1900 ccf DNA samples were performed to evaluate the technical feasibility of automating library preparation and increasing the sample multiplexing level. These processes were subsequently combined and a study of 1587 samples was completed to verify the stability of the process-optimized assay. Finally, an unblinded clinical evaluation of 1269 euploid and aneuploid samples utilizing this high-throughput assay coupled to improved bioinformatic procedures was performed. We were able to correctly detect all aneuploid cases with extremely low false positive rates of 0.09%, <0.01%, and 0.08% for trisomies 21, 18, and 13, respectively.ConclusionsThese data suggest that the developed laboratory methods in concert with improved bioinformatic approaches enable higher sample throughput while maintaining high classification accuracy.
| S-EPMC3590217 | biostudies-literature
Project description:We directly sequenced cell-free DNA with high-throughput shotgun sequencing technology from plasma of pregnant women, obtaining, on average, 5 million sequence tags per patient sample. This enabled us to measure the over- and underrepresentation of chromosomes from an aneuploid fetus. The sequencing approach is polymorphism-independent and therefore universally applicable for the noninvasive detection of fetal aneuploidy. Using this method, we successfully identified all nine cases of trisomy 21 (Down syndrome), two cases of trisomy 18 (Edward syndrome), and one case of trisomy 13 (Patau syndrome) in a cohort of 18 normal and aneuploid pregnancies; trisomy was detected at gestational ages as early as the 14th week. Direct sequencing also allowed us to study the characteristics of cell-free plasma DNA, and we found evidence that this DNA is enriched for sequences from nucleosomes.
| S-EPMC2562413 | biostudies-literature
Project description:BackgroundEquivocal findings exist regarding prenatal acetaminophen use and various adverse neonatal and childhood health outcomes, though with no data on fetal growth. We evaluated whether fetal growth differed by maternal acetaminophen use.MethodsRacially diverse, healthy women with low-risk antenatal profiles from 12 US clinical centers were enrolled in a prospective cohort study and followed until delivery. Ultrasound measurements of fetal parameters and self-reported prenatal acetaminophen use were collected at enrollment and up to five follow-up visits. Prenatal acetaminophen use was dichotomized as none or any.ResultsAmong 2291 women, 932 (41%) reported the use of acetaminophen medications during the current pregnancy. Estimated growth curves of fetal parameters did not differ between women reporting use of any medication containing acetaminophen and women with no reported use of the same.ConclusionAmong healthy mothers with low-risk pregnancies, maternal acetaminophen use was not associated with alterations in fetal growth.
| S-EPMC6658344 | biostudies-literature