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1.
Zhonghua Fu Chan Ke Za Zhi ; 55(10): 679-684, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33120479

RESUMO

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.


Assuntos
Ácidos Nucleicos Livres/genética , Transtornos Cromossômicos/diagnóstico , Doenças Fetais/diagnóstico , Diagnóstico Pré-Natal/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Trissomia/genética , Aneuploidia , Transtornos Cromossômicos/genética , DNA/genética , Feminino , Doenças Fetais/sangue , Doenças Fetais/genética , Humanos , Gravidez , Estudos Retrospectivos , Trissomia/diagnóstico
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1057-1060, 2020 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-32924100

RESUMO

OBJECTIVE: To assess the value of non-invasive prenatal testing (NIPT) for women with advanced gestational age but normal measurement for nuchal translucency (NT). METHODS: A total of 9371 singleton pregnancies with negative NT screening at early pregnancy were reviewed. Among these, 8627 cases were selected to be screened again by NIPT, and their indications and results were analyzed. The results were compared with those of with other high risk factors and young gestational age. RESULTS: The incidence of fetal aneuploidies increased in women with advanced gestational age and ultrasound soft markers, in particular among those who were negative for NT screening but over the age of 37. The detection rate of pathological or likely pathological copy number variations was 1.88% among women who directly underwent invasive prenatal diagnosis because of the advanced age, but there was no correlation with the increase of age. 0.68% of the women where with negative NT screening and NIPT still need to undergo invasive prenatal diagnosis. CONCLUSION: After NT screening in early pregnancy, NIPT can replace invasive prenatal diagnosis for those below the age of 37, though there is still a possibility of missed detection of pathogenic copy number variation. It is necessary to strengthen ultrasonic monitoring in later period.


Assuntos
Medição da Translucência Nucal , Diagnóstico Pré-Natal/métodos , Aneuploidia , Variações do Número de Cópias de DNA , Feminino , Humanos , Gravidez , Ultrassonografia Pré-Natal
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1061-1064, 2020 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-32924101

RESUMO

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The NIPT is effective for screening common chromosomal aneuploidies and preventing births of neonates with trisomy 21, trisomy 18 and trisomy 13.


Assuntos
Diagnóstico Pré-Natal/métodos , Trissomia/diagnóstico , Aneuploidia , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Feminino , Humanos , Recém-Nascido , Cariotipagem , Gravidez , Trissomia/genética , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1069-1073, 2020 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-32924103

RESUMO

OBJECTIVE: To assess the value of non-invasive prenatal testing (NIPT) for the screening of fetal chromosomal abnormalities. METHODS: For 12 085 pregnant women, the results of NIPT and invasive prenatal diagnosis were compared. RESULTS: The test was successful in 12 067 cases and has detected 179 chromosomal abnormalities, with a positive rate of 1.48%, sensitivity of 98.39% and specificity of 99.02%. Invasive prenatal diagnosis was performed for 3 of 18 patients who had failed NIPT but has detected no karyotypic abnormality. Except for one case of twin Cesarean section which delivered a normal female fetus and a stillbirth of unknown sex, the remainder of the 18 cases all had a normal delivery. The positive rate of NIPT screening for the abnormal ultrasound group was significant higher than that other groups (P< 0.01). Among those with positive results of NIPT, 122 underwent invasive prenatal diagnosis, and 25 trisomy 21, 7 trisomy 18, 3 trisomy 13, 4 aneuploidies of other autosomes, 13 sex chromosomal aneuploidies and 9 microdeletion/microduplications were confirmed, which yielded a positive predictive rate of 86.21%, 50.00%, 23.08%, 21.05%, 46.43%, and 47.36%, respectively. CONCLUSION: NIPT has high sensitivity, specificity and positive predictive value, and is an effective method for prenatal screening. In addition to chromosomes 21, 18 and 13, NIPT has certain predictive value for other autosomal aneuploidies, sex chromosomal aneuploidies, microdeletion/microduplications, and can provide a reference for karyotype analysis and chromosomal microarray verification.


Assuntos
Aberrações Cromossômicas , Diagnóstico Pré-Natal/métodos , Aneuploidia , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Feminino , Feto , Humanos , Cariótipo , Valor Preditivo dos Testes , Gravidez , Sensibilidade e Especificidade , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1117-1119, 2020 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-32924114

RESUMO

OBJECTIVE: To explore the value of in situ amniocyte culture for prenatal diagnosis. METHODS: 2716 amniotic fluid samples were cultured in situ on slides. After the culture, the slides were stained, photographed and analyzed. RESULTS: All samples were successfully analyzed, with the success rates for primary culture and subculture being 98.42% and 1.58%, respectively. 224 samples (8.25%) were detected with chromosomal aberrations, which included 125 cases with trisomy 21, 31 with trisomy 18, 3 with trisomy 13, 4 with 45,X, 17 with 47,XXY, 5 with 47,XYY, 1 with 48,XXY,+18, 1 with 48,XXYY, 26 with structural chromosomal aberrations, and 11 with mosaicisms for aneuploidies. CONCLUSION: In situ amniocyte culture is stable and has a high success rate, and is capable of identifying true and false mosaicisms, which can improve the accuracy of prenatal diagnosis.


Assuntos
Líquido Amniótico/citologia , Aberrações Cromossômicas , Transtornos Cromossômicos , Diagnóstico Pré-Natal , Aneuploidia , Transtornos Cromossômicos/diagnóstico , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez , Trissomia
6.
Cochrane Database Syst Rev ; 9: CD005291, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32898291

RESUMO

BACKGROUND: In in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI), selection of the most competent embryo(s) for transfer is based on morphological criteria. However, many women do not achieve a pregnancy even after 'good quality' embryo transfer. One of the presumed causes is that such morphologically normal embryos have an abnormal number of chromosomes (aneuploidies). Preimplantation genetic testing for aneuploidies (PGT-A), formerly known as preimplantation genetic screening (PGS), was therefore developed as an alternative method to select embryos for transfer in IVF. In PGT-A, the polar body or one or a few cells of the embryo are obtained by biopsy and tested. Only polar bodies and embryos that show a normal number of chromosomes are transferred. The first generation of PGT-A, using cleavage-stage biopsy and fluorescence in situ hybridisation (FISH) for the genetic analysis, was demonstrated to be ineffective in improving live birth rates. Since then, new PGT-A methodologies have been developed that perform the biopsy procedure at other stages of development and use different methods for genetic analysis. Whether or not PGT-A improves IVF outcomes and is beneficial to patients has remained controversial. OBJECTIVES: To evaluate the effectiveness and safety of PGT-A in women undergoing an IVF treatment. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in September 2019 and checked the references of appropriate papers. SELECTION CRITERIA: All randomised controlled trials (RCTs) reporting data on clinical outcomes in participants undergoing IVF with PGT-A versus IVF without PGT-A were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, assessed risk of bias, and extracted study data. The primary outcome was the cumulative live birth rate (cLBR). Secondary outcomes were live birth rate (LBR) after the first embryo transfer, miscarriage rate, ongoing pregnancy rate, clinical pregnancy rate, multiple pregnancy rate, proportion of women reaching an embryo transfer, and mean number of embryos per transfer. MAIN RESULTS: We included 13 trials involving 2794 women. The quality of the evidence ranged from low to moderate. The main limitations were imprecision, inconsistency, and risk of publication bias. IVF with PGT-A versus IVF without PGT-A with the use of genome-wide analyses Polar body biopsy One trial used polar body biopsy with array comparative genomic hybridisation (aCGH). It is uncertain whether the addition of PGT-A by polar body biopsy increases the cLBR compared to IVF without PGT-A (odds ratio (OR) 1.05, 95% confidence interval (CI) 0.66 to 1.66, 1 RCT, N = 396, low-quality evidence). The evidence suggests that for the observed cLBR of 24% in the control group, the chance of live birth following the results of one IVF cycle with PGT-A is between 17% and 34%. It is uncertain whether the LBR after the first embryo transfer improves with PGT-A by polar body biopsy (OR 1.10, 95% CI 0.68 to 1.79, 1 RCT, N = 396, low-quality evidence). PGT-A with polar body biopsy may reduce miscarriage rate (OR 0.45, 95% CI 0.23 to 0.88, 1 RCT, N = 396, low-quality evidence). No data on ongoing pregnancy rate were available. The effect of PGT-A by polar body biopsy on improving clinical pregnancy rate is uncertain (OR 0.77, 95% CI 0.50 to 1.16, 1 RCT, N = 396, low-quality evidence). Blastocyst stage biopsy One trial used blastocyst stage biopsy with next-generation sequencing. It is uncertain whether IVF with the addition of PGT-A by blastocyst stage biopsy increases cLBR compared to IVF without PGT-A, since no data were available. It is uncertain if LBR after the first embryo transfer improves with PGT-A with blastocyst stage biopsy (OR 0.93, 95% CI 0.69 to 1.27, 1 RCT, N = 661, low-quality evidence). It is uncertain whether PGT-A with blastocyst stage biopsy reduces miscarriage rate (OR 0.89, 95% CI 0.52 to 1.54, 1 RCT, N = 661, low-quality evidence). No data on ongoing pregnancy rate or clinical pregnancy rate were available. IVF with PGT-A versus IVF without PGT-A with the use of FISH for the genetic analysis Eleven trials were included in this comparison. It is uncertain whether IVF with addition of PGT-A increases cLBR (OR 0.59, 95% CI 0.35 to 1.01, 1 RCT, N = 408, low-quality evidence). The evidence suggests that for the observed average cLBR of 29% in the control group, the chance of live birth following the results of one IVF cycle with PGT-A is between 12% and 29%. PGT-A performed with FISH probably reduces live births after the first transfer compared to the control group (OR 0.62, 95% CI 0.43 to 0.91, 10 RCTs, N = 1680, I² = 54%, moderate-quality evidence). The evidence suggests that for the observed average LBR per first transfer of 31% in the control group, the chance of live birth after the first embryo transfer with PGT-A is between 16% and 29%. There is probably little or no difference in miscarriage rate between PGT-A and the control group (OR 1.03, 95%, CI 0.75 to 1.41; 10 RCTs, N = 1680, I² = 16%; moderate-quality evidence). The addition of PGT-A may reduce ongoing pregnancy rate (OR 0.68, 95% CI 0.51 to 0.90, 5 RCTs, N = 1121, I² = 60%, low-quality evidence) and probably reduces clinical pregnancies (OR 0.60, 95% CI 0.45 to 0.81, 5 RCTs, N = 1131; I² = 0%, moderate-quality evidence). AUTHORS' CONCLUSIONS: There is insufficient good-quality evidence of a difference in cumulative live birth rate, live birth rate after the first embryo transfer, or miscarriage rate between IVF with and IVF without PGT-A as currently performed. No data were available on ongoing pregnancy rates. The effect of PGT-A on clinical pregnancy rate is uncertain. Women need to be aware that it is uncertain whether PGT-A with the use of genome-wide analyses is an effective addition to IVF, especially in view of the invasiveness and costs involved in PGT-A. PGT-A using FISH for the genetic analysis is probably harmful. The currently available evidence is insufficient to support PGT-A in routine clinical practice.


Assuntos
Aneuploidia , Fertilização In Vitro , Testes Genéticos/métodos , Diagnóstico Pré-Implantação/métodos , Injeções de Esperma Intracitoplásmicas , Aborto Espontâneo/epidemiologia , Viés , Biópsia , Coeficiente de Natalidade , Blastocisto/patologia , Feminino , Humanos , Nascimento Vivo , Idade Materna , Corpos Polares/patologia , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 918-923, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820499

RESUMO

Although non-invasive prenatal testing has been widely used, it has certain limitations. As the gold standard of prenatal diagnosis, G-banding karyotype analysis is time-consuming and laborious. Fluorescence in situ hybridization (FISH), as a method for detecting samples with non-radioactive signals, does not require cell culture and has a short turnover time, and can diagnose aneuploidies of chromosomes 13, 18, 21, X, Y with efficiency, which can solve the problems such as insufficient testing ability and long diagnosis period for karyotype analysis. To standardize the procedures of prenatal FISH assay and enhance laboratory quality management, the Expert Committee of the Prenatal Screening and Diagnosis Laboratory of the Clinical Test Center of the National Health Commission and the Inter-laboratory Quality Assessment Committee of the Neonatal Genetic and Metabolic Disease Screening Laboratory have formulated this consensus.


Assuntos
Aneuploidia , Hibridização in Situ Fluorescente/normas , Diagnóstico Pré-Natal , Consenso , Feminino , Humanos , Cariotipagem , Gravidez
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 934-937, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820502

RESUMO

OBJECTIVE: To apply single cell sequencing based on multiple annealing and looping amplification cycles (MALBAC) for the determination of the rate and type of mosaicisms of high-quality embryos at cleavage stage. METHODS: After thawing and removing of zona pellucida by enzymatic digestion, blastomeres were collected the high-quality embryos donated by couples whom had given birth to healthy offspring by intracytoplasmic sperm injection and embryo transfer. The whole genome of single cell was amplified and subjected to next generation sequencing. RESULTS: From a total of 23 embryos, 184 blastomeres were collected. 175 (95.1%) of the blastomeres were successfully sequenced, of which 100 (57.1%) were found to harbor chromosomal aneuploidies. Among the 23 embryos, 3 (13.0%) were diploid, 20 (87.0%) were mosaicisms, which included 5 (21.7%) aneuploid mosaicisms, 7 (30.4%) diploid-aneuploid mosaicisms, 5 (21.7%) abnormal mosaicisms, and 3 (13.0%) irregular segregations. CONCLUSION: There is a high rate of chromosomal mosaicisms in high-quality cleavage embryos. Mosaicisms of complex chromosomal abnormality or with high proportion of abnormal cells may be an important factor affecting the potential of embryonic development.


Assuntos
Testes Genéticos , Mosaicismo , Diagnóstico Pré-Implantação , Análise de Célula Única , Aneuploidia , Blastômeros , Hibridização Genômica Comparativa , Feminino , Fertilização In Vitro , Humanos , Gravidez
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 891-894, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761603

RESUMO

OBJECTIVE: To explore the value of BACs-on-BeadsTM (BoBs) for the practice of prenatal diagnosis. METHODS: 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. RESULTS: 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. CONCLUSION: 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.


Assuntos
Transtornos Cromossômicos , Diagnóstico Pré-Natal/métodos , Aneuploidia , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Artificiais Bacterianos , Feminino , Humanos , Cariotipagem , Masculino , Gravidez
10.
Nat Commun ; 11(1): 3987, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778678

RESUMO

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.


Assuntos
Aneuploidia , Implantação do Embrião/genética , Embrião de Mamíferos , Desenvolvimento Embrionário , Antígenos CD/genética , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Pontos de Checagem do Ciclo Celular , Linhagem da Célula , Segregação de Cromossomos , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 21 , Feminino , Genes erbB-1/genética , Testes Genéticos , Humanos , Monossomia , Mosaicismo , Gravidez , Células-Tronco , Trissomia
11.
Mutat Res ; 785: 108320, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32800274

RESUMO

It is well established that maternal age is associated with a rapid decline in the production of healthy and high-quality oocytes resulting in reduced fertility in women older than 35 years of age. In particular, chromosome segregation errors during meiotic divisions are increasingly common and lead to the production of oocytes with an incorrect number of chromosomes, a condition known as aneuploidy. When an aneuploid oocyte is fertilized by a sperm it gives rise to an aneuploid embryo that, except in rare situations, will result in a spontaneous abortion. As females advance in age, they are at higher risk of infertility, miscarriage, or having a pregnancy affected by congenital birth defects such as Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Turner syndrome (monosomy X). Here, we review the potential molecular mechanisms associated with increased chromosome segregation errors during meiosis as a function of maternal age. Our review shows that multiple exogenous and endogenous factors contribute to the age-related increase in oocyte aneuploidy. Specifically, the weight of evidence indicates that recombination failure, cohesin deterioration, spindle assembly checkpoint (SAC) disregulation, abnormalities in post-translational modification of histones and tubulin, and mitochondrial dysfunction are the leading causes of oocyte aneuploidy associated with maternal aging. There is also growing evidence that dietary and other bioactive interventions may mitigate the effect of maternal aging on oocyte quality and oocyte aneuploidy, thereby improving fertility outcomes. Maternal age is a major concern for aneuploidy and genetic disorders in the offspring in the context of an increasing proportion of mothers having children at increasingly older ages. A better understanding of the mechanisms associated with maternal aging leading to aneuploidy and of intervention strategies that may mitigate these detrimental effects and reduce its occurrence are essential for preventing abnormal reproductive outcomes in the human population.


Assuntos
Aneuploidia , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos/genética , Anormalidades Congênitas/genética , Idade Materna , Anormalidades Congênitas/prevenção & controle , Feminino , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/genética , Meiose/genética , Mitocôndrias/fisiologia , Oócitos/fisiologia
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(7): 779-784, 2020 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-32619264

RESUMO

OBJECTIVE: 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. METHODS: 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. RESULTS: 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%. CONCLUSION: 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.


Assuntos
Variações do Número de Cópias de DNA , Cariotipagem , Diagnóstico Pré-Natal , Trissomia , Aneuploidia , Feminino , Humanos , Gravidez , Trissomia/diagnóstico , Trissomia/genética
13.
Medicine (Baltimore) ; 99(29): e20848, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702826

RESUMO

RATIONALE: Non-invasive prenatal testing (NIPT) is an accurate screening method with high specificity and sensitivity and a low false-positive rate of trisomy 21, 18, and 13. However, false-negative NIPT results could also limit the clinical application of NIPT. PATIENT CONCERNS: A 34-year-old primigravida woman who underwent NIPT at 16 + 3 weeks' gestation was identified as being at high risk for fetal trisomy X (47, XXX). Fetal cardiac defect and hand posture were observed during prenatal ultrasound examination at the 23rd week of gestation. DIAGNOSES: Amniocentesis conducted at the 24th week of gestation. Fetal karyotyping and FISH identified karyotype 48, XXX, + 18, which indicated that the NIPT failed to detect trisomy 18 in this case. INTERVENTIONS: The couple decided to terminate pregnancy at the 26th week of gestation and was willing to undergo further examinations. OUTCOMES: Discordant results between fetus with trisomy 18 and placenta with mosaic T18 were further identified with massive parallel sequencing, which might be due to that the fetal cell-free DNA in maternal plasma for NIPT that was assessed principally originated from the trophoblast cells. LESSONS: The presence of trisomy 18 mosaicism in the placenta might be the reason for the false-negative NIPT result in this case of double aneuploidy with 48, XXX, + 18, karyotype. Although the NIPT is a valuable screening method that has evident advantages in prenatal aneuploidy screening for certain chromosomal abnormalities compared to other methods, it is not a "diagnostic test" yet.


Assuntos
Aneuploidia , Testes Genéticos , Mosaicismo , Placenta , Diagnóstico Pré-Natal , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Amniocentese , Reações Falso-Negativas , Feminino , Humanos , Cariótipo , Gravidez , Análise de Sequência de DNA
14.
Cytogenet Genome Res ; 160(5): 225-237, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32659775

RESUMO

Loss of chromosome Y (LOY) is a mosaic aneuploidy that can be detected mainly in blood samples of male individuals. Usually, LOY occurrence increases with chronological age in healthy men. Moreover, recently LOY has been reported in association with several diseases, such as cancer, where its frequency is even higher. The Y chromosome is one of the shortest chromosomes of the human karyotype, and it is crucial for correct male development. This chromosome has functions beyond the male reproductive system, and loss of its genes or even LOY can have consequences for the male body that are yet to be elucidated. Analyses of the Y chromosome are largely applied in forensic contexts such as paternity testing, ancestry studies, and sexual assault cases, among others. Thus, LOY can be a disadvantage, limiting laboratory methods and result interpretation. However, as an advantage, LOY detection could be used as a biological age biomarker due to its association with the aging process. The potential application of LOY as biomarker highlights the necessity to clarify the molecular mechanism behind its occurrence and its possible applications in both health and forensic studies.


Assuntos
Aneuploidia , Cromossomos Humanos Y/genética , Medicina Legal , Marcadores Genéticos/genética , Saúde , Mosaicismo , Envelhecimento/genética , Haplótipos/genética , Humanos , Masculino , Paternidade , Delitos Sexuais
15.
Proc Natl Acad Sci U S A ; 117(29): 17031-17040, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632008

RESUMO

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.


Assuntos
Ribossomos/genética , Ribossomos/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Estresse Fisiológico/genética , Aneuploidia , Meio Ambiente , Regulação Fúngica da Expressão Gênica , RNA Fúngico/genética , RNA Fúngico/metabolismo , Análise de Sequência de RNA , Transcriptoma/genética
16.
Cochrane Database Syst Rev ; 7: CD013497, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32672358

RESUMO

BACKGROUND: GM-CSF (granulocyte macrophage colony-stimulating factor) is a growth factor that is used to supplement culture media in an effort to improve clinical outcomes for those undergoing assisted reproduction. It is worth noting that the use of GM-CSF-supplemented culture media often adds a further cost to the price of an in vitro fertilisation (IVF) cycle. The purpose of this review was to assess the available evidence from randomised controlled trials (RCTs) on the effectiveness and safety of GM-CSF-supplemented culture media. OBJECTIVES: To assess the effectiveness and safety of GM-CSF-supplemented human embryo culture media versus culture media not supplemented with GM-CSF, in women or couples undergoing assisted reproduction. SEARCH METHODS: We used standard methodology recommended by Cochrane. We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, LILACS, DARE, OpenGrey, PubMed, Google Scholar, and two trials registers on 15 October 2019, checked references of relevant papers and communicated with experts in the field. SELECTION CRITERIA: We included RCTs comparing GM-CSF (including G-CSF (granulocyte colony-stimulating factor))-supplemented embryo culture media versus any other non-GM-CSF-supplemented embryo culture media (control) in women undergoing assisted reproduction. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth and miscarriage rate. The secondary outcomes were clinical pregnancy, multiple gestation, preterm birth, birth defects, aneuploidy, and stillbirth rates. We assessed the quality of the evidence using GRADE methodology. We undertook one comparison, GM-CSF-supplemented culture media versus culture media not supplemented with GM-CSF, for those undergoing assisted reproduction. MAIN RESULTS: We included five studies, the data for three of which (1532 participants) were meta-analysed. We are uncertain whether GM-CSF-supplemented culture media makes any difference to the live-birth rate when compared to using conventional culture media not supplemented with GM-CSF (odds ratio (OR) 1.19, 95% confidence interval (CI) 0.93 to 1.52, 2 RCTs, N = 1432, I2 = 69%, low-quality evidence). The evidence suggests that if the rate of live birth associated with conventional culture media not supplemented with GM-CSF was 22%, the rate with the use of GM-CSF-supplemented culture media would be between 21% and 30%. We are uncertain whether GM-CSF-supplemented culture media makes any difference to the miscarriage rate when compared to using conventional culture media not supplemented with GM-CSF (OR 0.75, 95% CI 0.41 to 1.36, 2 RCTs, N = 1432, I2 = 0%, low-quality evidence). This evidence suggests that if the miscarriage rate associated with conventional culture media not supplemented with GM-CSF was 4%, the rate with the use of GM-CSF-supplemented culture media would be between 2% and 5%. Furthermore, we are uncertain whether GM-CSF-supplemented culture media makes any difference to the following outcomes: clinical pregnancy (OR 1.16, 95% CI 0.93 to 1.45, 3 RCTs, N = 1532 women, I2 = 67%, low-quality evidence); multiple gestation (OR 1.24, 95% CI 0.73 to 2.10, 2 RCTs, N = 1432, I2 = 35%, very low-quality evidence); preterm birth (OR 1.20, 95% CI 0.70 to 2.04, 2 RCTs, N = 1432, I2 = 76%, very low-quality evidence); birth defects (OR 1.33, 95% CI 0.59 to 3.01, I2 = 0%, 2 RCTs, N = 1432, low-quality evidence); and aneuploidy (OR 0.34, 95% CI 0.03 to 3.26, I2 = 0%, 2 RCTs, N = 1432, low-quality evidence). We were unable to undertake analysis of stillbirth, as there were no events in either arm of the two studies that assessed this outcome. AUTHORS' CONCLUSIONS: Due to the very low to low quality of the evidence, we cannot be certain whether GM-CSF is any more or less effective than culture media not supplemented with GM-CSF for clinical outcomes that reflect effectiveness and safety. It is important that independent information on the available evidence is made accessible to those considering using GM-CSF-supplemented culture media. The claims from marketing information that GM-CSF has a positive effect on pregnancy rates are not supported by the available evidence presented here; further well-designed, properly powered RCTs are needed to lend certainty to the evidence.


Assuntos
Meios de Cultura/química , Fertilização In Vitro/métodos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Aborto Espontâneo/epidemiologia , Aneuploidia , Viés , Intervalos de Confiança , Anormalidades Congênitas/epidemiologia , Feminino , Humanos , Nascimento Vivo , Gravidez , Taxa de Gravidez , Gravidez Múltipla/estatística & dados numéricos , Nascimento Prematuro/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Técnicas de Reprodução Assistida
17.
Nature ; 583(7815): 259-264, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32494014

RESUMO

Meiosis, although essential for reproduction, is also variable and error-prone: rates of chromosome crossover vary among gametes, between the sexes, and among humans of the same sex, and chromosome missegregation leads to abnormal chromosome numbers (aneuploidy)1-8. To study diverse meiotic outcomes and how they covary across chromosomes, gametes and humans, we developed Sperm-seq, a way of simultaneously analysing the genomes of thousands of individual sperm. Here we analyse the genomes of 31,228 human gametes from 20 sperm donors, identifying 813,122 crossovers and 787 aneuploid chromosomes. Sperm donors had aneuploidy rates ranging from 0.01 to 0.05 aneuploidies per gamete; crossovers partially protected chromosomes from nondisjunction at the meiosis I cell division. Some chromosomes and donors underwent more-frequent nondisjunction during meiosis I, and others showed more meiosis II segregation failures. Sperm genomes also manifested many genomic anomalies that could not be explained by simple nondisjunction. Diverse recombination phenotypes-from crossover rates to crossover location and separation, a measure of crossover interference-covaried strongly across individuals and cells. Our results can be incorporated with earlier observations into a unified model in which a core mechanism, the variable physical compaction of meiotic chromosomes, generates interindividual and cell-to-cell variation in diverse meiotic phenotypes.


Assuntos
Genoma Humano/genética , Meiose/genética , Espermatozoides/citologia , Espermatozoides/metabolismo , Adolescente , Adulto , Alelos , Aneuploidia , Troca Genética/genética , Haplótipos/genética , Humanos , Masculino , Não Disjunção Genética , Análise de Célula Única , Doadores de Tecidos , Adulto Jovem
18.
Am J Hum Genet ; 107(2): 325-329, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574563

RESUMO

Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed for detecting mosaic variants. We found 160 individuals that carry >10 Mb copy number changes, including 56 with whole chromosome aneuploidies. Nineteen (12%) individuals had a diagnosis of Down syndrome or other developmental disorder, while 84 (52.5%) individuals had a diagnosis of hematological malignancies or chronic myeloproliferative disorders. Notably, there was no evidence of mosaicism in the blood for many of these large CNVs, so they could easily be mistaken for germline alleles even when caused by somatic mutations. We therefore suggest that somatic mutations associated with blood cancers may result in false estimates of rare variant penetrance from population biobanks.


Assuntos
Variações do Número de Cópias de DNA/genética , Hematopoese/genética , Adulto , Idoso , Alelos , Aneuploidia , Bancos de Espécimes Biológicos , Cromossomos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Mutação/genética , Penetrância , Reino Unido
19.
Nat Commun ; 11(1): 2958, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528010

RESUMO

The high incidence of aneuploidy in the embryo is considered the principal cause for low human fecundity. However, the prevalence of aneuploidy dramatically declines as pregnancy progresses, with the steepest drop occurring as the embryo completes implantation. Despite the fact that the plasticity of the embryo in dealing with aneuploidy is fundamental to normal development, the mechanisms responsible for eliminating aneuploid cells are unclear. Here, using a mouse model of chromosome mosaicism, we show that aneuploid cells are preferentially eliminated from the embryonic lineage in a p53-dependent process involving both autophagy and apoptosis before, during and after implantation. Moreover, we show that diploid cells in mosaic embryos undertake compensatory proliferation during the implantation stages to confer embryonic viability. Together, our results indicate a close link between aneuploidy, autophagy, and apoptosis to refine the embryonic cell population and ensure only chromosomally fit cells proceed through development of the fetus.


Assuntos
Aneuploidia , Apoptose/fisiologia , Autofagia/fisiologia , Animais , Apoptose/genética , Autofagia/genética , Proliferação de Células/genética , Proliferação de Células/fisiologia , Diploide , Implantação do Embrião , Embrião de Mamíferos/metabolismo , Embriologia , Desenvolvimento Embrionário/fisiologia , Feminino , Imunofluorescência , Camadas Germinativas/metabolismo , Camundongos , Mosaicismo
20.
Am J Surg Pathol ; 44(8): 1017-1030, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32568823

RESUMO

A robust morphomolecular classification system for gastric carcinoma is required. A 4-tier morphologic classification is proposed, including diffuse, intestinal, tubular, and lymphoid types. A tissue microarray for mismatch repair immunohistochemistry and Epstein-Barr virus (EBV) in situ hybridization were performed in 329 gastric carcinomas. DNA flow cytometry was used to detect aneuploidy in formalin-fixed paraffin-embedded samples. Lymphoid histology was the third most common histologic pattern at our institute and strongly associated with EBV infection and PMS2/MLH1-deficiency (both P<0.001). HER2 overexpression and SATB2 expression more frequently occurred in intestinal histology (both P<0.001). Loss of ARID1A expression was strikingly associated with lymphoid histology (P<0.001) and negative E-cadherin expression was correlated with diffuse histology (P=0.001). Programmed death-ligand 1 expression was most frequently present in lymphoid-type gastric carcinoma than other histologic subtypes and correlated with the molecular features of PMS2/MLH1-deficiency and EBV infection (all P<0.001). Aneuploidy was detected in 53% of gastric carcinomas and was highly correlated with intestinal type and the least with the lymphoid type (P<0.001). Notably, lymphoid-type gastric carcinoma showed the best outcome, whereas tubular type showed the worst survival rate (P<0.001). We integrated aneuploidy with morphologic patterns to propose a morphomolecular classification scheme, which served as a successful and independent prognostic factor in multivariate 5-year disease-free survival analysis (P<0.001). Overall, we describe an integrated morphomolecular classification system for gastric carcinomas to effectively predict patient outcomes. This system is cost-effective and reliable and can help select target therapeutics and facilitate clinical management.


Assuntos
Adenocarcinoma/química , Adenocarcinoma/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Gástricas/química , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Adenocarcinoma/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Reparo de Erro de Pareamento de DNA , Intervalo Livre de Doença , Feminino , Herpesvirus Humano 4/genética , Humanos , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/análise , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/análise , Proteína 1 Homóloga a MutL/análise , Estadiamento de Neoplasias , Receptor ErbB-2/análise , Fatores de Risco , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Taiwan , Fatores de Tempo , Fatores de Transcrição/análise , Adulto Jovem
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