Common Aneuploidies Research Articles

Reanalysis of discarded blastocysts for autosomal aneuploidy after sex selection in cleavage-stage embryos.

ObjectiveThe goal of the present study was to investigate the rate of chromosomal aneuploidies in surplus embryos after sex determination at the cleavage stage. Then, the same chromosomal aneuploidies were evaluated in blastocysts after extended culture.MethodsSixty-eight surplus embryos were biopsied at the cleavage stage and incubated for an additional 3 days to allow them to reach the blastocyst stage. The embryos were reanalyzed via fluorescence in situ hybridization (FISH) to examine eight chromosomes (13, 15, 16, 18, 21, 22, X, and Y) in both cleavage-stage embryos and blastocysts.ResultsAlthough the total abnormality rate was lower in blastocysts (32.35%) than in cleavage-stage embryos (45.58%), the difference was not significant (p=0.113). However, when we restricted the analysis to autosomal abnormalities, we observed a significant difference in the abnormality rate between the cleavage-stage embryos (44.11%) and the blastocysts (17.64%, p=0.008). A higher rate of sex chromosomal abnormalities was also observed in cleavage-stage embryos (29.4%) than in blastocysts (14.70%, p=0.038).ConclusionThe data indicated that embryo biopsy should be conducted at the blastocyst stage rather than the cleavage stage. The results also emphasized that examination of common chromosomal aneuploidies apart from sex selection cycles can be conducted in the blastocyst stage with the FISH method.

CHROMOSOMAL DISEASES IN THE HUMAN PATHOLOGY

Background. Chromosomal diseases are the cause of 45-50 % of multiple birth defects. Basic research on mutations is performed using genomic technologies to identify a correlation between genotype and phenotype in aneuploidies and to understand its pathogenesis.
 Objective. The aim of the research is to study the etiology, pathogenesis of symptoms and diagnostics for patients with Down, Klinefelter, Turner syndromes and double aneuploidies by 21 and sex chromosomes.
 Methods. A literature review by the keywords “Down syndrome”, “Klinefelter syndrome”, “Turner syndrome”, “double aneuploidy” for the period of 2000-2020 was carried out.
 Results. Down, Klinefelter and Turner syndromes are the most common aneuploidy among viable newborns. Frequency of meiotic non-disjunction events causing these aneuploidies increases with the age of a woman. Identified genes are responsible for pathogenesis of symptoms in trisomy 21, Turner and Klinefelter syndromes. Diagnostics of chromosomal diseases includes prenatal screening programs and postnatal testing.
 Conclusions. Cytogenetic variants of Down syndrome are simple complete trisomy 21, translocation form and mosaicism. Trisomy 21 is associated with advanced maternal age. Phenotypic manifestations of Down syndrome are associated with the locus 21q22. The maternal and parental nondisjunction of X-chromosomes in meiosis causes Klinefelter and Turner syndromes. These chromosomal diseases are variants of intersexualism with intermediate chromosomal sex. Down-Klinefelter and Down-Turner syndromes are double aneuploidies. Patients have a Down syndrome phenotype at birth, and signs of Klinefelter and Turner syndromes occur during puberty. Diagnosis of aneuploidy is based on the cytogenetic investigation (karyotyping), DNA analysis, ultrasonography and biochemical markers of chromosomal pathology.

Absent Cavum Septi Pellucidi

Absent Cavum Septi Pellucidi

Dandy-Walker Malformation

Dandy-Walker Malformation

Concomitant Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Discovered by Flow Cytometry

Abstract Casestudy: Chronic lymphocytic leukemia (CLL) accounts for about 30% of all lymphoid neoplasms and is the most common adult blood cancer in the Western world. Mantle cell lymphoma (MCL) accounts for only about 6% of all B-cell lymphomas in Western countries. MCL and CLL are both CD5 positive B-cell lymphoproliferative disorders. It is necessary to distinguish these two entities as MCL is a more aggressive disease, and requires specific treatment. MCL and CLL can occur in one patient at the same time and is often termed a composite lymphoma. We present an 84-year-old female with a history of endometrial cancer who was found to have splenomegaly and lymphadenopathy. Flow cytometry was performed upon her peripheral blood specimen which demonstrated two distinct populations of abnormal light chain restricted B-cell populations. One population demonstrated kappa light chain restriction and was positive for CD45, CD19, CD20, CD5, CD38, FMC-7, and CD22, representing MCL. The other population showed dim lambda light chain restriction that was also positive for CD45, CD19, dim CD20, CD5, and CD23, representing CLL. FISH studies demonstrated t(11;14), and four common deletions or chromosome aneuploidy associated with CLL. These findings confirmed the dual populations of CLL and MCL. This is an interesting case because it is a very rare combination with only a few cases having been reported with two distinct cell populations in one patient at the same time.

Concomitant Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Discovered by Flow Cytometry

Abstract Casestudy: Chronic lymphocytic leukemia (CLL) accounts for about 30% of all lymphoid neoplasms and is the most common adult blood cancer in the Western world. Mantle cell lymphoma (MCL) accounts for only about 6% of all B-cell lymphomas in Western countries. MCL and CLL are both CD5 positive B-cell lymphoproliferative disorders. It is necessary to distinguish these two entities as MCL is a more aggressive disease, and requires specific treatment. MCL and CLL can occur in one patient at the same time and is often termed a composite lymphoma. We present an 84-year-old female with a history of endometrial cancer who was found to have splenomegaly and lymphadenopathy. Flow cytometry was performed upon her peripheral blood specimen which demonstrated two distinct populations of abnormal light chain restricted B-cell populations. One population demonstrated kappa light chain restriction and was positive for CD45, CD19, CD20, CD5, CD38, FMC-7, and CD22, representing MCL. The other population showed dim lambda light chain restriction that was also positive for CD45, CD19, dim CD20, CD5, and CD23, representing CLL. FISH studies demonstrated t(11;14), and four common deletions or chromosome aneuploidy associated with CLL. These findings confirmed the dual populations of CLL and MCL. This is an interesting case because it is a very rare combination with only a few cases having been reported with two distinct cell populations in one patient at the same time.

Confirmation and analysis of 2 398 positive results of cell-free fetal DNA

Objective: To explore the clinical application value and accuracy of cell-free fetal DNA (cff-DNA) technique in prenatal screening. Methods: The results of quantitative fluorescent PCR (QF-PCR) and karyotype of amniotic fluid cells were analyzed retrospectively in 2 398 monocyesis pregnant women who had been amniocentesis at the First Affiliated Hospital of Zhengzhou University from May 2013 to December 2019, and the results of 359 cases who had been examined by single-nucleotide polymorphism array (SNP array). Results: Cff-DNA test of 2, 398 cases indicated 987 cases of trisomy 21, 351 cases of trisomy 18, 135 cases of trisomy 13, 566 cases of sex chromosome abnormality, and 359 cases of other chromosome abnormality. Chromosome karyotype analysis detected 826 cases of trisomy 21, 213 cases of trisomy 18, 17 cases of trisomy 13, 221 cases of sex chromosome abnormality, and 26 cases of other chromosome abnormality. The detection rate were 83.69% (826/987), 60.68% (213/351), 12.59% (17/135), 39.04% (221/566) and 7.24% (26/359), respectively. QF-PCR detected 1 046 cases of trisomy and 188 cases of sex chromosomes abnormality, and the detection rate was 99.05% (1 046/1 056) and 85.07% (188/221), respectively. Compared with the abnormal number detected by chromosome karyotype analysis, 10 cases of trisomeric chimerism and 24 cases of sex chromosome were missed by QF-PCR. Among the 359 other chromosomal abnormalities detected by SNP array, 64 cases were consistent with the results of cff-DNA, and the detection rate was 17.83% (64/359), which was 10.59% higher than the karyotype result. Conclusions: Karyotype analysis is the gold standard for diagnosing chromosomal abnormalities. QF-PCR could diagnose common chromosome aneuploidy rapidly and accurately, and it could be used as an auxiliary detection technique for karyotype analysis. The incidence of sex chromosome chimerism is high, so missed diagnosis should be warned. SNP array could be given priority to verify chromosome microdeletion or microduplication detected by cff-DNA.

Clinical significance of non-invasive prenatal testing in preventing birth defects

To assess the performance of non-invasive prenatal testing (NIPT) for the detection of fetal chromosomal aneuploidies and its value for the prevention of birth defects. In total 28 033 pregnant women underwent NIPT test. The results were compared with that of amniotic fluid and cord blood chromosomal karyotyping analysis. A few cases were verified by array comparative genome hybridization (aCGH). All pregnant women and their fetuses were followed up until after birth. NIPT has indicated a high risk for fetal chromosomal aneuploidies in 186 cases (0.66%), among which 101 (67.33%) were confirmed as 21, 18 and 13 trisomies by invasive prenatal diagnosis, which yielded a diagnostic rate of 86.52%, 50.00% and 19.05%, respectively. The diagnostic rates were 81.28%, 67.85%, 62.79% and 76.00% respectively for those ≥40, ≥35, 25 to 34, and <25. And the diagnostic rates were 65.91%, 60.78%, 71.79% and 80.00% for those over 35, with high risk by prenatal screening, critical risk by prenatal screening and ultrasound abnormality, respectively. The NIPT is effective for screening common chromosomal aneuploidies and preventing births of neonates with trisomy 21, trisomy 18 and trisomy 13.

Application of BACs-on-BeadsTM in prenatal diagnosis

To explore the value of BACs-on-BeadsTM (BoBs) for the practice of prenatal diagnosis. The results of chromosomal karyotyping and BoBs of 1773 prenatal samples were compared. Microdeletions and microduplications detected by BoBs were subjected to chromosome microarray analysis (CMA) with informed consent from patients. BoBs has detected 46 cases of common aneuploidies involving chromosomes 13, 18, and 21, and 16 cases involving X and Y chromosomes. For 4 fetuses with normal results by BoBs, karyotyping analysis of amniotic fluid sample suggested low percentage mosaicisms (< 20%). BoBs has detected none of the 9 common microdeletions, but 14 male fetuses with Xp22 microdeletions and 5 with other microdeletions/microduplications. In 10 cases, the couples had chosen CMA verification, and the results were all consistent. As a rapid diagnostic technique, BoBs has a high accuracy for common aneuploidies, and is capable of discovering certain chromosome microdeletions and microduplications. The difficulty lies in the inability to detect low proportion mosaicisms and the consultation following detection for male fetuses carrying Xp22 microdeletions.

Genetic study of a trisomy 13 fetus with a false-negative karyotype by chorionic villi analysis

To explore the mechanism of a false-negative result from karyotyping of chorionic villi cells for a trisomy 13 fetus featuring multiple malformations. For a fetus with multiple malformations by ultrasonography and a 46,XY karyotype by chorionic villi analysis, amniocytes were further analyzed with quantitative fluorescence PCR (QF-PCR), G-banded karyotyping and chromosomal microarray analysis (CMA). Meanwhile, non-invasive prenatal testing (NIPT) was conducted on peripheral blood sample from the pregnant woman to determine the chromosomal composition of cytotrophoblast. After induction of labor, common aneuploidies in placenta and fetal tissue were also analyzed by QF-PCR. QF-PCR, chromosomal karyotyping and CMA analysis of the amniocytes all suggested complete trisomy 13 (47,XY,+13) in the fetus. NIPT also suggested existence of fetal trisomy 13. QF-PCR analysis of the placenta and fetal tissues revealed that cells derived from the maternal surface and right side of fetal surface harbored mosaic trisomy 13, while those derived from other sites of fetal surface of the placenta, umbilical cord, amniotic membrane and fetal muscle tissue harbored trisomy 13. Karyotyping of long-term cultured chorionic villus sample may give rise to false negative results due to placental mosaicism. To ensure accurate prenatal diagnosis, discordance between karyotyping of chorionic villi cells, fetal ultrasound and NIPT result should be verified by amniocentesis or cordocentesis and application of multiple cytogenetic and molecular techniques.

Developmental potential of aneuploid human embryos cultured beyond implantation

Aneuploidy, the presence of an abnormal number of chromosomes, is a major cause of early pregnancy loss in humans. Yet, the developmental consequences of specific aneuploidies remain unexplored. Here, we determine the extent of post-implantation development of human embryos bearing common aneuploidies using a recently established culture platform. We show that while trisomy 15 and trisomy 21 embryos develop similarly to euploid embryos, monosomy 21 embryos exhibit high rates of developmental arrest, and trisomy 16 embryos display a hypo-proliferation of the trophoblast, the tissue that forms the placenta. Using human trophoblast stem cells, we show that this phenotype can be mechanistically ascribed to increased levels of the cell adhesion protein E-CADHERIN, which lead to premature differentiation and cell cycle arrest. We identify three cases of mosaicism in embryos diagnosed as full aneuploid by pre-implantation genetic testing. Our results present the first detailed analysis of post-implantation development of aneuploid human embryos.

A Comprehensive Clinical Genetics Approach to Critical Congenital Heart Disease in Infancy

To investigate the frequency of genetic diagnoses among infants with critical congenital heart disease (CHD) using a comprehensive cardiovascular genetics approach and to identify genotype-phenotype correlations. A retrospective chart review of patients evaluated by cardiovascular genetics in a pediatric cardiac intensive care unit from 2010 to 2015 was performed. Infants with CHD who were <1month of age were included. CHD was classified using structured phenotype definitions. Cardiac and noncardiac phenotypes were tested for associations with abnormal genetic testing using χ1 and Fisher exact tests. Genetic evaluation was completed in 293 infants with CHD, of whom 213 had isolated congenital heart disease (iCHD) and 80 had multiple congenital anomalies. Overall, the yield of abnormal genetic testing was 26%. The multiple congenital anomalies cohort had a greater yield of genetic testing (39%) than the iCHD cohort (20%) (OR 2.7). Using a non-hierarchical CHD classification and excluding 22q11.2 deletion and common aneuploidies, right ventricular obstructive defects were associated with abnormal genetic testing (P=.0005). Extracardiac features associated with abnormal genetic testing included ear, nose, and throat (P=.003) and brain (P=.0001) abnormalities. A diagnosis of small for gestational age or intrauterine growth retardation also was associated with abnormal genetic testing (P=.0061), as was presence of dysmorphic features (P=.0033, OR 3.5). Infants without dysmorphia with iCHD or multiple congenital anomalies had similar frequencies of abnormal genetic testing. The present study provides evidence to support a comprehensive cardiovascular genetics approach in evaluating infants with critical CHD while also identifying important genotype-phenotype considerations.

Application of high-throughput sequencing technology for the detection of fetal copy number variations

To assess the value of non-invasive prenatal testing (NIPT) for the detection of fetal copy number variations (CNVs) in addition to trisomies 21, 18, and 13. A total of 37 306 pregnant women underwent the NIPT test. For those with fetal CNVs indicated by NIPT and accepted invasive prenatal diagnosis, amniotic fluid samples were obtained for chromosomal karyotyping analysis and chromosome microarray analysis (CMA). All cases were followed up. Among the 37 306 cases, 78 (0.209%) were predicted to have fetal CNVs. Among these, 52 pregnant women accepted invasive prenatal diagnosis, and 15 of them (28.85%) obtained a consistent result. Follow up of 26 women who refused invasive prenatal diagnosis have found 2 cases with spontaneous abortion, 2 with induced labor for fetal malformation indicated by ultrasonography, and 1 had multiple malformations and a consistent result by CMA, which yielded an abnormal rate of 19.23%. NIPT can signal fetal chromosomal abnormalities through detection of gain and/or loss of fetal DNA copies. Combined chromosomal karyotyping and CMA can increase the detection rate for common chromosomal aneuploidies and CNVs, thereby provide a basis for genetic counseling for the affected families.

Expression profile of microRNAs in the testes of patients with Klinefelter syndrome

Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy. A distinctive characteristic of KS is oligozoospermia. Despite multiple studies that have described the natural history of the degenerative process of germ cells in patients with KS, the molecular mechanisms that initiate this process are not well characterized. MicroRNA (miRNA)-mediated post-transcriptional control mechanisms have been increasingly recognized as important regulators of spermatogenesis; however, only a few studies have evaluated the role of miRNAs in the gonadal failure of these patients. Here, we describe a differential expression profile for the miRNAs in testicular tissue samples taken from KS patients. We analysed testicular tissue samples from 4 KS patients and 5 control patients (obstructive azoospermia) through next-generation sequencing, which can provide information about the mechanisms involved in the degeneration of germ cells. A distinctive differential expression profile was identified for 166 miRNAs in the KS patients: 66 were upregulated, and 100 were downregulated. An interactome analysis was performed for 7 of the upregulated and the 20 downregulated miRNAs. The results showed that the target genes are involved in the development, proliferation, and differentiation processes of spermatogenesis, which may explain their role in the development of infertility. This is the first report of a miRNA expression profile generated from testicular tissue samples of KS patients.

A rare Down syndrome foetus with de novo 21q;21q rearrangements causing false negative results in non-invasive prenatal testing: a case report

BackgroundNon-invasive prenatal testing (NIPT) has been established as a routine prenatal screening to assess the risk of common foetal aneuploidy disorder (trisomy 21, 18, and 13). NIPT has high sensitivity and high specificity, but false positive and false negative results still exist. False negative NIPT results involving Down syndrome are rare, but have a high clinical impact on families and society.Case presentationWe described a case of a foetus that tested “negative” for trisomy 21 (Z-score was 0.664) by NIPT based on the semiconductor sequencing platform (SSP). The foetal fraction of cell-free DNA was 16.9%; this percentage was much larger than the threshold of 4% for obtaining accurate NIPT results. However, postnatally, the newborn was diagnosed with Down syndrome with the 46,XY,der(21;21)(q10;q10),+ 21 karyotype.ConclusionsWe presented a case of false negative NIPT results, which may occur through biological mechanisms rather than poor quality, technical errors or negligence. It is imperative for clinical geneticists and their patients to understand that NIPT is still a screening test.

The environmental stress response causes ribosome loss in aneuploid yeast cells

Aneuploidy, a condition characterized by whole chromosome gains and losses, is often associated with significant cellular stress and decreased fitness. However, how cells respond to the aneuploid state has remained controversial. In aneuploid budding yeast, two opposing gene-expression patterns have been reported: the "environmental stress response" (ESR) and the "common aneuploidy gene-expression" (CAGE) signature, in which many ESR genes are oppositely regulated. Here, we investigate this controversy. We show that the CAGE signature is not an aneuploidy-specific gene-expression signature but the result of normalizing the gene-expression profile of actively proliferating aneuploid cells to that of euploid cells grown into stationary phase. Because growth into stationary phase is among the strongest inducers of the ESR, the ESR in aneuploid cells was masked when stationary phase euploid cells were used for normalization in transcriptomic studies. When exponentially growing euploid cells are used in gene-expression comparisons with aneuploid cells, the CAGE signature is no longer evident in aneuploid cells. Instead, aneuploid cells exhibit the ESR. We further show that the ESR causes selective ribosome loss in aneuploid cells, providing an explanation for the decreased cellular density of aneuploid cells. We conclude that aneuploid budding yeast cells mount the ESR, rather than the CAGE signature, in response to aneuploidy-induced cellular stresses, resulting in selective ribosome loss. We propose that the ESR serves two purposes in aneuploid cells: protecting cells from aneuploidy-induced cellular stresses and preventing excessive cellular enlargement during slowed cell cycles by down-regulating translation capacity.

Performance of non-invasive prenatal screening for sex chromosome aneuploidies and parental decision-making.

Performance of non-invasive prenatal screening for sex chromosome aneuploidies and parental decision-making.

Clinical Performance of Cell-Free Fetal DNA Testing for Fetal Aneuploidies and Subchromosomal Deletions/Duplications in a Cohort of 19,531 Pregnancies

Objective: We aim to assess the clinical performance of cell-free fetal DNA (cffDNA) testing for detecting common fetal aneuploidies as well as subchromosomal deletions/duplications and explore the pregnancy decisions in screen-positive cases. Methods: A cohort of 19,531 pregnant women was offered cffDNA testing for detection of trisomies 21, 18, and 13 (T21, T18, and T13); sex chromosome aneuploidies (SCAs); and subchromosomal deletions/duplications. Screen-positive cases were confirmed by karyotyping and single-nucleotide polymorphism array analysis. Results: A total of 47 cases failed the test. The overall screen-positive rate of chromosomal abnormalities was 1.07% (208/19,484), including 57 cases with T21, 18 cases with T18, 7 cases with T13, 106 cases with SCAs, and 20 cases of subchromosomal deletions/duplications. Positive predictive values were 91.30% (42/46), 38.46% (5/13), 33.33% (2/6), 41.33% (31/75), and 27.78% (5/18), respectively. There was no significant difference in the screening of fetal chromosomal aneuploidies in the high-risk group compared with the low-risk group (P > 0.05). All of the pregnant women who had confirmed fetal T21, T18, or T13 terminated their pregnancies, except for a case of T13 mosaic, whereas 45.16% (14/31) of women with fetal SCAs continued their pregnancies. Furthermore, 17 pregnant women with positive screens for T21, T18, or T13 without a subsequent diagnosis chose to terminate their pregnancy, whereas 29 of 31 women with SCAs chose to continue their pregnancies. Conclusions: CffDNA testing exhibited good screening accuracy for T21, T18, and T13 and also contributed to detecting fetal SCAs and subchromosomal deletions/duplications. Pregnant women with fetal 47, XXX or 47, XYY were more willing to terminate their pregnancy than those with fetal 45, X or 47, XXY.

Rare sex chromosome variation 48,XXYY: An integrative review.

While the most common Sex Chromosome Aneuploidy (SCA) is 47,XXY, other variations, such as 48,XXYY, are less studied, perhaps due to its rarity. 48,XXYY occurs with an estimated prevalence of 1:18,000-40,000 male births. This SCA is associated with a variety of complex physical, psychological, and neuroanatomical findings. The purpose of this integrative review is to summarize the available evidence related to 48,XXYY and identify gaps in the literature. This study utilized integrative review and PRISMA-guided methodology to search six databases for information pertaining to 48,XXYY. There were no exclusion criteria related to design methodology, given the paucity of available research. Among 397 articles reviewed for potential inclusion, 30 articles remained after inclusion and exclusion criteria were applied. Seven of these articles concentrated solely on participants with 48,XXYY. Literature was summarized into categories of physical phenotype, psychosocial, behavioral, neurocognitive, and brain function. Clinical description of 48,XXYY has evolved over time to develop a deeper understanding of this complex disorder. Large gaps remain, especially a lack of experimental studies, clinical guidelines, and treatments. Additionally, few studies explore methodologies such as interviews or self-report surveys in this population. 48,XXYY presents with a wide spectrum of physical, psychological, and neurocognitive symptoms, and frequently requires complex interdisciplinary care. In order to better understand this disorder and to appropriately treat the individuals affected by it, future research should focus on experimental studies and research that utilizes a variety of methods, including participant interviews and patient-report surveys.

Antenatal detection of chromosomal abnormalities combining QF-PCR and cytogenetic analysis

Aim: To compare the diagnostic values and limitations of quantitative fluorescent polymerase chain reaction (QF-PCR) and conventional cytogenetic analysis in prenatal diagnosis of chromosomal abnormalities. Methods: A prospective study included simultaneous QF-PCR and cytogenetic analysis of 133 prenatal samples routinely obtained by amniocentesis or chorionic villus sampling (CVS). Additionally, QF-PCR analysis was performed on 14 tissue samples collected after termination of pregnancy (TOP) for which karyotyping could not be performed due to culture failure. Results: Among 133 analyzed prenatal samples, chromosomal abnormalities were diagnosed in 12 cases (9%), including 10 cases of numerical chromosomal aberrations and two cases with unbalanced structural rearrangements. Nine out of 12 chromosomal abnormalities were also detected with QF-PCR. However, all cases of major aneuploidies were successfully disclosed with QF-PCR, resulting in 100% detection rate for chromosomes 21, 18, 13, X and Y. Using a set of markers specific for chromosomes 21, 18 and 13, QF-PCR analysis of tissues collected after TOP revealed chromosomopathy in 21.4% of cases (two cases of trisomy 18 and one triploidy). A comparison of STR markers confirmed monozygosity in two monochorionic/diamniotic twin pregnancies. Conclusion: QF-PCR has been shown as a rapid and reliable method for prenatal diagnosis of the most common chromosomal aneuploidies, and as an adequate alternative to conventional karyotyping in cases where cytogenetic analysis is not possible due to failure of culturing process. However, conventional cytogenetics still presents a gold standard for the detection of structural aberrations and rare aneuploidies.