Cell-free DNA testing in a trisomy 21 pregnancy with confined placental mosaicism for a cell line with trisomy for both chromosomes 18 and 21.
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ABSTRACT:
SUBMITTER: Crooks K
PROVIDER: S-EPMC4706389 | biostudies-other | 2016 Jan
REPOSITORIES: biostudies-other
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Project description:ObjectivesWe wanted to re-evaluate the influence of confined placental mosaicism subtypes (type 2 and type 3) on pregnancy characteristics and outcome.Material and methodsFrom July 2009 to December 2015, 5512 chorionic villus samplings were performed in our Fetal Medicine Center. Conventional karyotyping was performed after long-term and short-term cultured villi to define type 2 or type 3 confined placental mosaicisms. Karyotype after amniocentesis was performed to exclude true fetal mosaicism, when appropriate. Pregnancy characteristics and outcomes were collected and compared to a control population.ResultsThirty-six (0.65%) confined placental mosaicisms were observed (13 type 2 and 23 type 3). Nuchal translucency was not increased for type 2 and type 3 confined placental mosaicisms. Pregnancy characteristics and outcomes were comparable between type 2 confined placental mosaicisms and the control population. In type 3 confined placental mosaicisms, median first trimester serum pregnancy-associated plasma protein A was lower than for the control population (p<0.001), preterm births were noticed in 56% (p<0.001), small for gestational age newborns in 74% (p<0.001), and adverse pregnancy outcome was reported in 35% (p<0.01).ConclusionAlthough type 2 confined placental mosaicisms appeared to have no influence on pregnancy characteristics and outcome, type 3 confined placental mosaicisms were associated with low levels of first trimester serum pregnancy-associated plasma protein A, preterm birth, small for gestational age newborns, and adverse pregnancy outcomes.
| S-EPMC5897023 | biostudies-literature
Project description:BackgroundChromosomal mosaicism can be detected in different stages of early life: in cleavage stage embryos, in blastocysts and biopsied cells from blastocysts during preimplantation genetic testing for aneuploidies (PGT-A) and later during prenatal testing, as well as after birth in cord blood. Mosaicism at all different stages can be associated with adverse pregnancy outcomes. There is an onward discussion about whether blastocysts diagnosed as chromosomally mosaic by PGT-A should be considered safe for transfer. An accurate diagnosis of mosaicism remains technically challenging and the fate of abnormal cells within an embryo remains largely unknown. However, if aneuploid cells persist in the extraembryonic tissues, they can give rise to confined placental mosaicism (CPM). Non-invasive prenatal testing (NIPT) uses cell-free (cf) DNA released from the placenta in maternal blood, facilitating the detection of CPM. In literature, conflicting evidence is found about whether CPM is associated with fetal growth restriction (FGR) and/or other pregnancy outcomes. This makes counselling for patients by clinicians challenging and more knowledge is needed for clinical decision and policy making.Objective and rationaleThe objective of this review is to evaluate the association between CPM and prenatal growth and adverse pregnancy outcomes. All relevant literature has been reviewed in order to achieve an overview on merged results exploring the relation between CPM and FGR and other adverse pregnancy outcomes.Search methodsThe following Medical Subject Headings (MESH) terms and all their synonyms were used: placental, trophoblast, cytotrophoblast, mosaicism, trisomy, fetal growth, birth weight, small for gestational age and fetal development. A search in Embase, PubMed, Medline Ovid, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar databases was conducted. Relevant articles published until 16 July 2020 were critically analyzed and discussed.OutcomesThere were 823 articles found and screened based on their title/abstract. From these, 213 articles were selected and full text versions were obtained for a second selection, after which 70 publications were included and 328 cases (fetuses) were analyzed. For CPM in eight different chromosomes (of the total 14 analyzed), there was sufficient evidence that birth weight was often below the 5th percentile of fetal growth standards. FGR was reported in 71.7% of CPM cases and preterm birth (<37 weeks of delivery) was reported in 31.0% of cases. A high rate of structural fetal anomalies, 24.2%, in cases with CPM was also identified. High levels of mosaicism in CVS and presence of uniparental disomy (UPD) were significantly associated with adverse pregnancy outcomes.Wider implicationsBased on the literature, the advice to clinicians is to monitor fetal growth intensively from first trimester onwards in case of CPM, especially when chromosome 2, 3, 7, 13, 15, 16 and 22 are involved. In addition to this, it is advised to examine the fetuses thoroughly for structural fetal anomalies and raise awareness of a higher chance of (possibly extreme) premature birth. Despite prematurity in nearly a fifth of cases, the long-term follow-up of CPM life borns seems to be positive. More understanding of the biological mechanisms behind CPM will help in prioritizing embryos for transfer after the detection of mosaicism in embryos through PGT-A.
| S-EPMC8382909 | biostudies-literature
Project description:Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer's disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.
| S-EPMC5570437 | biostudies-other
Project description:BackgroundMolecular size determination of circulating free fetal DNA in maternal plasma is an important detection method for noninvasive prenatal testing (NIPT). The fetal DNA molecule is the primary factor determining the overall performance of NIPT and its clinical interpretation. The proportion of cell-free fetal DNA molecules is expressed as the fetal DNA fraction in the plasma of pregnant women.MethodsWe proposed an effective method to deduce fetal chromosomal aneuploidy based on the proportion of a certain range of DNA fragment lengths from maternal plasma. We gradually narrowed the range of the upper and lower boundary via a traversing algorithm.ResultsWe explored the optimal range of the upper and lower boundary by using size-based DNA fragment length. Using this range, the accuracy of the sensitivity and specificity could be improved by up to 100% for detecting the three most common autosomal aneuploidies, namely trisomy 13, trisomy 18, trisomy 21 in the sample set.ConclusionsNumerical experiments demonstrate that our method is effective and efficient. The program is available upon request.
| S-EPMC6461288 | biostudies-literature
Project description:BACKGROUND:Maternal uniparental disomy of chromosome 6 (upd(6)mat) is a rare finding and its clinical relevance is currently unclear. Based on clinical data from two new cases and patients from the literature, the pathogenetic significance of upd(6)mat is delineated. METHODS:Own cases were molecularly characterized for isodisomic uniparental regions on chromosome 6. For further cases with upd(6)mat, a literature search was conducted and genetic and clinical data were ascertained. RESULTS:Comparison of isodisomic regions between the new upd(6)mat cases and those from four reports did not reveal any common isodisomic region. Among the patients with available cytogenetic data, five had a normal karyotype in lymphocytes, whereas a trisomy 6 (mosaicism) was detected prenatally in four cases. A common clinical picture was not obvious in upd(6)mat, but intrauterine growth restriction (IUGR) and preterm delivery were frequent. CONCLUSION:A common upd(6)mat phenotype is not obvious, but placental dysfunction due to trisomy 6 mosaicism probably contributes to IUGR and preterm delivery. In fact, other clinical features observed in upd(6)mat patients might be caused by homozygosity of recessive mutations or by an undetected trisomy 6 cell line. Upd(6)mat itself is not associated with clinical features, and can rather be regarded as a biomarker. In case upd(6)mat is detected, the cause for the phenotype is identified indirectly, but the UPD is not the basic cause.
| S-EPMC5702562 | biostudies-literature
Project description:The aim of this study is to survey somatic mutations in human placentas.
| EGAS00001003549 | EGA
Project description:The presence of multiple large (>1 Mb) copy number variants (CNVs) in non-malignant tissue is rare in human genetics. We present a liveborn male with a birth weight below the first percentile associated with placental mosaicism involving eight 2.4-3.9 Mb de novo duplications. We found that the duplications likely co-localized to the same cells, were mosaic in the placenta, and impacted maternal and paternal chromosomes. In addition, 27.4 Mb and 240 genes were duplicated in affected cells, including candidate placental genes KISS1 and REN. We ruled out involvement of homologous recombination-based mechanisms or an altered epigenome in generating the CNVs. This case highlights the diversity of genetic abnormalities in the human placenta and the gaps in our knowledge of how such errors arise.
| S-EPMC8251599 | biostudies-literature
Project description:OBJECTIVE:Recent non-invasive prenatal testing (NIPT) technologies are based on next-generation sequencing (NGS). NGS allows rapid and effective clinical diagnoses to be determined with two common sequencing systems: Illumina and Ion Torrent platforms. The majority of NIPT technology is associated with Illumina platform. We investigated whether fetal trisomy 18 and 21 were sensitively and specifically detectable by semiconductor sequencer: Ion Proton. METHODS:From March 2012 to October 2013, we enrolled 155 pregnant women with fetuses who were diagnosed as high risk of fetal defects at Xiamen Maternal & Child Health Care Hospital (Xiamen, Fujian, China). Adapter-ligated DNA libraries were analyzed by the Ion Proton™ System (Life Technologies, Grand Island, NY, USA) with an average 0.3× sequencing coverage per nucleotide. Average total raw reads per sample was 6.5 million and mean rate of uniquely mapped reads was 59.0%. The results of this study were derived from BWA mapping. Z-score was used for fetal trisomy 18 and 21 detection. RESULTS:Interactive dot diagrams showed the minimal z-score values to discriminate negative versus positive cases of fetal trisomy 18 and 21. For fetal trisomy 18, the minimal z-score value of 2.459 showed 100% positive predictive and negative predictive values. The minimal z-score of 2.566 was used to classify negative versus positive cases of fetal trisomy 21. CONCLUSION:These results provide the evidence that fetal trisomy 18 and 21 detection can be performed with semiconductor sequencer. Our data also suggest that a prospective study should be performed with a larger cohort of clinically diverse obstetrics patients.
| S-EPMC4203771 | biostudies-literature
Project description:Fetal congenital heart disease (CHD) is often associated with chromosomal abnormalities. Our primary aim was to assess stillbirth and neonatal mortality rates for pregnancies complicated by trisomies 13, 18, and 21 in the presence of CHD, from a single tertiary referral center during 2000-2020 in a retrospective cohort study. The secondary aims were to investigate maternal morbidity in these pregnancies, and to study the gestational or neonatal age when mortality occurred. Inclusion criteria were the prenatal diagnosis of at least one structural CHD, together with prenatally diagnosed fetal trisomy 13, 18, or 21. One-hundred and sixty patients with fetal trisomy 13 (14.4%), fetal trisomy 18 (28.8%), and fetal trisomy 21 (56.9%) were evaluated. In total, 98 (61.3%) families opted for the termination of pregnancy (TOP). Of the remaining 62 (38.8%) pregnancies, 16 (25.8%) resulted in intrauterine fetal death/death during delivery. Ten out of twenty-one (47.6%) infants with trisomy 13 or 18 were born alive. The livebirth rate was 87.8% (36/41) for infants with trisomy 21. Early neonatal death was observed in nine (19.6%) infants. Thirty-one (86.1%) infants with trisomy 21 survived the first year of life. These data may be helpful for counseling affected parents when the decision to terminate or continue the pregnancy should be considered.
| S-EPMC9410270 | biostudies-literature
Project description:Eukaryotic genomes are organised into complex higher-order structures within the nucleus, and the three-dimensional arrangement of chromosomes is functionally important for global gene regulation. The existence of supernumerary chromosome 21 in Down syndrome may perturb the nuclear architecture at different levels, which is normally optimised to maintain the physiological balance of gene expression. However, it has not been clearly elucidated whether and how aberrant configuration of chromosomes affects gene activities. To investigate the effects of trisomy 21 on nuclear organisation and gene expression, we performed three-dimensional fluorescent imaging analysis of chromosome-edited human induced pluripotent stem cells (iPSCs), which enabled identification of the parental origin of the three copies of chromosome 21. We found that two copies of maternal chromosomes resulting from meiotic nondisjunction had a higher tendency to form an adjacent pair and were located relatively distant from the nuclear membrane, suggesting the conserved interaction between these homologous chromosomes. Transcriptional profiling of parental-origin-specific corrected disomy 21 iPSC lines indicated upregulated expression of the maternal alleles for a group of genes, which was accompanied by a fluctuating expression pattern. These results suggest the unique effects of a pair of maternal chromosomes in trisomy 21, which may contribute to the pathological phenotype.
| S-EPMC5429678 | biostudies-literature