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RESEARCH QUESTION: Are intrinsic or extrinsic factors associated with embryo mosaicism prevalence in IVF cycles? DESIGN: Retrospective cohort study of preimplantation genetic testing for aneuploidy (PGT-A) cycles carried out at a university-affiliated IVF clinic between October 2017 and October 2019. Trophectoderm biopsies were analysed by next generation sequencing. Mosaicism prevalence, type of anomaly and the chromosomes involved were analysed. Intrinsic and extrinsic factors potentially inducing mosaicism were studied: maternal and paternal age, antral follicle count, cumulus-oocyte complexes retrieved, female body mass index, PGT-A indication, sperm concentration, total dosage of gonadotrophins, embryo quality and day of blastocyst formation, single-step commercial media used and biopsy operator. RESULTS: Overall prevalence of mosaicism in our PGT-A setting was 13.9%. In segmental mosaicism, larger chromosomes tended to be more affected, which was not observed in whole-chromosome mosaicism. Additionally, segmental mosaicism was mostly observed in monosomy (69.6%; P < 0.01) compared with whole-chromosome mosaicism (49.7% monosomies versus 50.3% trisomies; Pâ¯=â¯0.83). Although a high inter-patient variability was observed, only paternal age showed a positive association with mosaicism (adjusted OR 1.26, 95% CI 1.02 to 1.54) among the analysed variables. CONCLUSIONS: Our results suggest remarkable differences in the mechanisms generating segmental and whole-chromosome mosaicism, indicating that they may deserve different consideration when studying them and when prioritizing them for transfer. Male factor seems to be associated with mosaicism and may be worthy of specific assessment in future studies.
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Aneuploidia , Blastocisto/patología , Mosaicismo/estadística & datos numéricos , Diagnóstico Preimplantación/estadística & datos numéricos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
RESEARCH QUESTION: Preimplantation genetic testing for aneuploidies has increasingly been employed for embryo selection, resulting in a recent surge in mosaic embryos. According to the cytogenetic results, which types of mosaic embryo survive early pregnancy, progress to the second trimester and finally result in a live birth? DESIGN: This study evaluated 30,587 pregnant women undergoing amniocentesis from January 2004 to March 2020 at the cytogenic centre of Kaohsiung Chang Gung Memorial Hospital. Samples from amniocentesis were cultured using the in-situ method. The types and distribution of level III chromosomal mosaicism (two or more cells with the same abnormality in two or more colonies and both culture dishes, clinically referred to as 'true mosaicism') were retrospectively reviewed. RESULTS: Among the 30,587 women, 78 cases (0.26%) of level III chromosomal mosaicism were identified. The types of chromosomal mosaicism were classified as sex chromosome mosaicism (SCM), autosomal chromosome mosaicism (ACM) and marker chromosome mosaicism (MCM), with SCM, ACM and MCM accounting for 58.97%, 32.05% and 8.97% of cases, respectively. The most common mosaic cell lines were monosomy X and trisomy 21. The most common mosaic cell line progressing to live birth was monosomy X. CONCLUSIONS: Mosaic monosomy X and trisomy 21 are the most common cell lines of true mosaicism determined by amniocentesis. Monosomy X mosaicism is the most common cell line in live births. For women considering the transfer of these types of mosaic embryo in a circumstance where euploid embryos are unavailable, clinicians should provide careful prenatal counselling, detailed ultrasonography and amniocentesis.
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Síndrome de Down , Mosaicismo/estadística & datos numéricos , Diagnóstico Preimplantación/estadística & datos numéricos , Síndrome de Turner , Amniocentesis/estadística & datos numéricos , Femenino , Humanos , Embarazo , Estudios RetrospectivosRESUMEN
RESEARCH QUESTION: What is the incidence of complex mosaic in preimplantation genetic testing (PGT) blastocysts and can it be managed in clinical practice? DESIGN: A retrospective study of PGT cycles conducted between January 2018 and October 2019 at a single centre. Biopsies of blastocysts were collected and analysed by next-generation sequencing (NGS). Complex mosaic blastocysts were defined as those with three or more mosaic chromosomes. The cryopreserved complex mosaic blastocysts underwent a second round of biopsy, NGS analysis and vitrification. The euploid blastocysts identified by the re-biopsy were warmed again for embryo transfer. The main outcomes included the prevalence of the complex mosaic and the ongoing pregnancy rate. RESULTS: The prevalence of the complex mosaic was 2.4% (437/17,979). The prevalence of the complex mosaic was not associated with maternal age and morphological quality. A total of 89 complex mosaic blastocysts underwent re-biopsy and 96.6% (86/89) survived the first warming. For the re-biopsy samples, 61.6% (53/86) were euploid. The poor-quality blastocysts had higher rates of aneuploidy compared with good-quality blastocysts. The survival rate for blastocysts undergoing the second warming was 100% (18/18) and resulted in an ongoing pregnancy rate of 38.9% (7/18) as well as the birth of six healthy infants. CONCLUSION: Re-biopsy may rescue blastocysts with development potential for transfer and improve the cumulative pregnancy rate per stimulation cycle in patients containing complex mosaic blastocysts.
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Blastocisto/patología , Infertilidad/diagnóstico , Mosaicismo , Adulto , Biopsia , Blastocisto/metabolismo , Aberraciones Cromosómicas/embriología , Aberraciones Cromosómicas/estadística & datos numéricos , Criopreservación , Transferencia de Embrión/estadística & datos numéricos , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Infertilidad/epidemiología , Infertilidad/genética , Infertilidad/terapia , Mosaicismo/embriología , Mosaicismo/estadística & datos numéricos , Embarazo , Índice de Embarazo , Diagnóstico Preimplantación/estadística & datos numéricos , Prevalencia , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , VitrificaciónRESUMEN
OBJECTIVE: To examine the relationship between the fraction of cell-free DNA (cfDNA) affected by aneuploidy compared to the overall fetal fraction of a prenatal screening specimen and its effect on positive predictive value (PPV). METHOD: CfDNA specimens positive for trisomy 13, 18, and 21 with diagnostic outcomes were analysed over a 22-month period in one clinical laboratory. For each positive specimen, a "mosaicism ratio" (MR) was calculated by dividing the fraction of cfDNA affected by aneuploidy by the overall fetal fraction of the specimen. PPVs were calculated and analyzed based on various MR ranges. RESULTS: Trisomy 13 was the aneuploidy most commonly seen in mosaic form, followed by trisomy 18 and trisomy 21. Significant differences in positive predictive values were noted for all three trisomies between samples with an MR in the "mosaic" versus "non-mosaic" range, as well as between results classified as "low-mosaic" versus "high-mosaic." CONCLUSION: PPVs may be influenced, in part, by the mosaicism ratio associated with a particular result. The data generated from this study may be useful in providing more personalized risk assessments for patients with positive cfDNA screening results.
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Ácidos Nucleicos Libres de Células/análisis , Pruebas de Detección del Suero Materno/estadística & datos numéricos , Mosaicismo/estadística & datos numéricos , Trisomía/diagnóstico , Adulto , Estudios de Cohortes , Femenino , Humanos , Valor Predictivo de las Pruebas , Embarazo , Trisomía/genéticaRESUMEN
OBJECTIVE: To evaluate the prevalence of mosaicism in chorionic villus sampling (CVS) samples after chromosomal microarray (CMA) and clinical outcome of pregnancies affected by confined placental mosaicism. METHOD: We retrieved all results from CMA, array-based comparative genomic hybridization, on CVS samples from January 2011 to November 2017 from Central and North Denmark Regions. Mosaic results from uncultured chorionic villi, cytotrophoblasts and mesenchymal cells, after CVS and follow-up on amniocytes, fetal tissue, or postnatal blood were studied and matched with clinical data from The Danish Fetal Medicine Database. RESULTS: Prevalence of mosaicism was 93 out of 2,288 (4.1%) CVS samples of which 17 (18.3%) concerned submicroscopic copy number variations (CNVs) <10 Mb. Follow-up analyses were performed in 62 cases. True fetal mosaicism (TFM) was confirmed in 18.4% (7/38) when mosaicism involved whole chromosome aneuploidy and in 25.0% (6/24), when involving a CNV (P = .59). Median birth weight z-score was higher in cases of confined placental mosaicism for a CNV (0.21) than cases involving whole chromosomes (-0.74) (P = .02). CONCLUSION: Prevalence of mosaicism in CVS samples is higher after CMA on uncultured tissue than after conventional karyotyping on cultured tissue. The risk of TFM is equally high in cases of mosaicism for CNVs and whole chromosomes.
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Trastornos de los Cromosomas/epidemiología , Mesodermo/citología , Mosaicismo/estadística & datos numéricos , Placenta/metabolismo , Trofoblastos/metabolismo , Aborto Inducido , Aborto Espontáneo , Adulto , Células Cultivadas , Vellosidades Coriónicas/metabolismo , Muestra de la Vellosidad Coriónica , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Dinamarca/epidemiología , Síndrome de Down/epidemiología , Femenino , Humanos , Recién Nacido , Cariotipificación , Nacimiento Vivo , Masculino , Pruebas de Detección del Suero Materno , Mesodermo/metabolismo , Análisis por Micromatrices , Medida de Translucencia Nucal , Embarazo , Prevalencia , Estudios Retrospectivos , Síndrome de la Trisomía 18/epidemiologíaRESUMEN
Aim: The aim of this study is to summarize the outcomes of transfers of mosaic embryos, which were classified according to guidelines and in strong collaboration of reproductologists, clinical geneticists and patients approved as suitable for transfer. Material and Methods: Retrospective data were collected from 70 patients from a private IVF center to whom embryos with mosaic changes in chromosomal material were transferred from 2015 to 2019. Results and Conclusion: Implantation outcomes and continuing pregnancies showed slight differences, when compared to fully normal embryos. Artifacts have to be differentiated from undeniable aberrations, and correct interpretation of results must be done with following patient counselling and prenatal testing if necessary.
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Transferencia de Embrión/estadística & datos numéricos , Mosaicismo/estadística & datos numéricos , Resultado del Embarazo/epidemiología , Adulto , Estudios de Casos y Controles , Femenino , Clínicas de Fertilidad , Fertilización In Vitro/estadística & datos numéricos , Pruebas Genéticas/estadística & datos numéricos , Historia del Siglo XXI , Humanos , Letonia/epidemiología , Mosaicismo/embriología , Embarazo , Diagnóstico Preimplantación/estadística & datos numéricos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess the impact of non-invasive prenatal testing (NIPT) on trends in the prenatal diagnosis of sex chromosome aneuploidy (SCA) in a population with >73,000 annual births. METHOD: Retrospective population-based cohort study from 1986-2016 of all women undergoing prenatal diagnosis before 25 weeks gestation in the Australian state of Victoria. Statistical significance was tested using the chi-square test for trend or proportions. RESULTS: There were 2,043,345 births and 842 SCA diagnoses from 1986-2016. The percentage of prenatal diagnostic tests leading to a SCA diagnosis increased significantly from 0.95% in 2010 to 2.93% in 2016 (p < 0.001) but due to a concurrent decline in testing, the annual prenatal diagnosis rate of SCA remained stable at 4.4/10,000 births. Among confirmed fetal SCAs the most common indication for testing in 1986 was advanced maternal age (63%); in 2016 it was high risk NIPT (49%). CONCLUSION: SCAs now make up an increasing proportion of prenatal diagnostic results but due to the overall decline in diagnostic testing, the prenatal prevalence as a percentage of births remained steady. The ascertainment of fetal SCA has evolved from an incidental finding after testing for increased risk of trisomy 21, to a diagnosis obtained after suspected SCA on NIPT.
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Aneuploidia , Síndrome de Klinefelter/epidemiología , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/epidemiología , Síndrome de Turner/epidemiología , Cariotipo XYY/epidemiología , Adulto , Amniocentesis , Muestra de la Vellosidad Coriónica , Cromosomas Humanos X , Femenino , Humanos , Síndrome de Klinefelter/diagnóstico , Mosaicismo/estadística & datos numéricos , Embarazo , Diagnóstico Prenatal , Estudios Retrospectivos , Aberraciones Cromosómicas Sexuales/estadística & datos numéricos , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/diagnóstico , Trisomía/diagnóstico , Síndrome de Turner/diagnóstico , Ultrasonografía Prenatal , Victoria/epidemiología , Cariotipo XYY/diagnósticoRESUMEN
BACKGROUND: Advanced paternal and/or maternal age is a classic risk factor for Down syndrome. The aim of the study was to investigate the frequency of Down syndrome types in children and its association with maternal and paternal age in Bosnia and Herzegovina. SUBJECTS AND METHODS: The cross sectional, observational study included 127 children, 49 girls and 78 boys, aged 1-180 months suspected to have Down syndrome, admitted to the Centre for Genetics, Faculty of Medicine University of Sarajevo, for cytogenetic analysis and differential diagnosis of Down syndrome during the period from January 2010 to May 2015. Standard method of 72 hours cultivation of peripheral blood lymphocytes has been applied. The accepted level of statistical significance was p<0.05. STUDY RESULTS: The most common type of Down syndrome was standard trisomy (86.6%), comparing to translocation and mosaicism (7.1%; 6.3%, respectively). The highest frequency of Down syndrome cases was in mother and father's group from 30-39 years old (57; 57 children, respectively) compared to mother and father's groups with younger than 30 (44; 29, respectively) and 40 and older (26; 41, respectively). The significant difference was found in maternal age between translocation and mosaicism groups (p=0.036). Difference between parental years and type of Down syndrome was significant when Standard trisomy 21 and translocation (p=0.045), as well as mosaicism and translocation (p=0.036), were compared. CONCLUSION: The most common type of Down syndrome was standard trisomy 21, with highest occurrence in parents from 30 to 39 years old. Parents were the youngest in translocation group. Obtained results suggest that multidisciplinary approach to identifying the trigger for trisomy appearance and the influence of maternal age is required.
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Síndrome de Down , Edad Materna , Mosaicismo , Edad Paterna , Translocación Genética , Adolescente , Adulto , Distribución por Edad , Bosnia y Herzegovina/epidemiología , Preescolar , Estudios Transversales , Síndrome de Down/epidemiología , Síndrome de Down/genética , Femenino , Frecuencia de los Genes , Humanos , Incidencia , Lactante , Masculino , Persona de Mediana Edad , Mosaicismo/estadística & datos numéricos , Factores de Riesgo , Distribución por Sexo , Translocación Genética/genética , Adulto JovenRESUMEN
OBJECTIVE: The risk of clinical consequences in prenatal cases with de novo small supernumerary marker chromosomes (sSMC), often in mosaic conditions, is not easy to predict, which results in difficulties in genetic counseling. METHOD: In this study, we evaluated the frequency, the chromosomal origin, and the clinical indication of 104 de novo sSMC detected in a monocenter survey on the basis of 143,000 consecutive prenatal diagnoses, and we assessed the reliability of molecular cytogenetics technologies for sSMC characterization. RESULTS: We detected a de novo sSMC frequency of 0.072%. Its incidence in advanced maternal age group is statistically different from that found in maternal anxiety indication (<35 years old). A higher prevalence of mosaicism in chorionic villi sampling (CVS) than in amniotic fluids was also revealed related to confined placental mosaicisms. The risk of confirmation in amniotic fluids of mosaics previously revealed at CVS was 33.3%. No uniparental disomy conditions were found when imprinted chromosomes were involved in the occurrence of de novo sSMC. The majority of de novo sSMC were acrocentric derived-chromosomes, and a neocentromere formation was observed in one pregnancy. CONCLUSION: Our data support that array comparative genomic hybridization has improved sSMC characterization and demonstrate its utility in supporting genetic counseling. We propose a workflow for de novo sSMC characterization.
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Aberraciones Cromosómicas/estadística & datos numéricos , Análisis Citogenético/métodos , Mosaicismo/estadística & datos numéricos , Diagnóstico Prenatal , Adulto , Cromosomas , Hibridación Genómica Comparativa/métodos , Hibridación Genómica Comparativa/estadística & datos numéricos , Análisis Citogenético/estadística & datos numéricos , Femenino , Marcadores Genéticos , Humanos , Incidencia , Masculino , Embarazo , Reproducibilidad de los ResultadosAsunto(s)
Algoritmos , Cromosomas Humanos X , Feto/metabolismo , Monosomía/diagnóstico , Mosaicismo , Diagnóstico Prenatal , Adulto , Aberraciones Cromosómicas/estadística & datos numéricos , Cromosomas Humanos X/genética , Reacciones Falso Positivas , Femenino , Feto/patología , Humanos , Pruebas de Detección del Suero Materno/métodos , Pruebas de Detección del Suero Materno/estadística & datos numéricos , Monosomía/genética , Mosaicismo/estadística & datos numéricos , Madres/estadística & datos numéricos , Embarazo , Diagnóstico Prenatal/métodos , Diagnóstico Prenatal/estadística & datos numéricos , Síndrome de Turner/diagnóstico , Síndrome de Turner/epidemiologíaRESUMEN
OBJECTIVE: The purpose of this study is to investigate the potential genetic alterations at DNA level in patients with ovarian endometriosis by high-resolution array-based comparative genomic hybridization (array-CGH) analysis. METHODS: Following the laparoscopic surgical and the post-operative pathological examination, genomic DNA was extracted from endometriomas of 11 women with endometriosis and endometrial tissue of the controls and analyzed by array-CGH. Real-time PCR was used for confirmation the result of array-CGH analysis and detected the DNA copy number variations of the eutopic endometrium from the five patients with the duplication in 20q13.33 region. RESULTS: All 11 patients with ovarian endometriosis were diagnosed through the laparoscopic surgical and the post-operative pathological examination. We found occurrence of genomic duplication at 20q13.33 chromosomal region with gain of GATA5 and SLCO4A1 genes in 5 of 11 endometriomas from patients. CONCLUSION: The results of the present study suggest that there was 20q13.33 duplication in women with ovarian endometriosis. This effect might be due to the alterations of GATA5 and SLCO4A1 genes in the gain region, through involving the metabolism of the steroid hormone.
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Cromosomas Humanos Par 20/genética , Hibridación Genómica Comparativa , Endometriosis/genética , Enfermedades del Ovario/genética , Trisomía/diagnóstico , Adulto , Pueblo Asiatico/estadística & datos numéricos , Estudios de Casos y Controles , Hibridación Genómica Comparativa/métodos , Variaciones en el Número de Copia de ADN , Endometriosis/epidemiología , Femenino , Perfilación de la Expresión Génica/métodos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Mosaicismo/estadística & datos numéricos , Enfermedades del Ovario/epidemiología , Trisomía/genética , Adulto JovenRESUMEN
OBJECTIVE: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in â¼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome. METHODS: An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations. RESULTS: Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms. CONCLUSION: Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.
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Proteínas Portadoras/genética , Síndromes Periódicos Asociados a Criopirina/genética , Mosaicismo/estadística & datos numéricos , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Proteína con Dominio Pirina 3 de la Familia NLRRESUMEN
OBJECTIVE: To study the influence of types 2 and 3 confined placental mosaicism (CPM) on pregnancy outcome. METHOD: From 13 809 chorionic villus samplings (CVSs), karyotype after long-term cultured villi (LTC-villi) was systematically performed. Next, in case of suspicion of CPM, karyotype after short-term cultured villi (STC-villi) was established to define type 2 CPM (chromosomal abnormality limited to the mesenchymal core) or type 3 CPM (chromosomal abnormality found both in the cytotrophoblast and the mesenchymal core). Confirmatory amniocentesis was performed to exclude fetal mosaicism. Uniparental disomy (UPD) testing was carried out when the abnormal cell line involved chromosomes 5, 6, 7, 15 or 16. RESULTS: Fifty-seven CPM cases were observed (57/13 809 = 0.41%) and of these, 37 were type 2 and 20 were type 3 CPM. Incidence of preterm infants, neonatal hypotrophy and adverse pregnancy outcome were comparable between patients in whom type 2 CPM was demonstrated and the control population. In contrast, for the type 3 CPM the incidence of these factors was higher than for the control population. CONCLUSION: When a CPM is suspected, it appears essential to determine type, since type 2 has no effect on fetal development and type 3 is associated with preterm infants, low birth weight and adverse pregnancy outcome.
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Mosaicismo/clasificación , Placenta/metabolismo , Resultado del Embarazo/genética , Aborto Eugénico/estadística & datos numéricos , Adulto , Aneuploidia , Muestra de la Vellosidad Coriónica/estadística & datos numéricos , Aberraciones Cromosómicas/estadística & datos numéricos , Síndrome de Down/epidemiología , Síndrome de Down/genética , Femenino , Humanos , Recién Nacido , Enfermedades del Recién Nacido/epidemiología , Enfermedades del Recién Nacido/genética , Mosaicismo/estadística & datos numéricos , Embarazo , Resultado del Embarazo/epidemiología , Estudios RetrospectivosRESUMEN
Recently it has been suggested that the human brain contains aneuploid cells; however the nature and magnitude of neural aneuploidy in health and disease remain obscure. Here, we have monitored aneuploidy in the cerebral cortex of the normal, Alzheimer's disease (AD) and ataxia telangiectasia (AT) brain by molecular cytogenetic approaches scoring more than 480,000 neural cells. Using arbitrarily selected set of DNA probes for chromosomes 1, 7, 11, 13, 14, 17, 18, 21, X and Y we have determined the mean rate of stochastic aneuploidy per chromosome as 0.5% in the normal human brain (95%CI 0.2-0.7%; SD 0.2%). The overall proportion of aneuploid cells in the normal brain has been estimated at approximately 10%. In the AT brain, we observed a 2-to-5 fold increase of stochastic aneuploidy randomly affecting different chromosomes (mean 2.1%; 95%CI - 1.5-2.6%; SD 0.8%). The overall proportion of aneuploid cells in the brain of AT individuals was estimated at approximately 20-50%. Compared with sex- and age-matched controls, the level of stochastic aneuploidy in the AD brain was not significantly increased. However, a dramatic 10-fold increase of chromosome 21-specific aneuploidy (both hypoploidy and hyperploidy) was detected in the AD cerebral cortex (6-15% versus 0.8-1.8% in control). We conclude that somatic mosaic aneuploidy differentially contributes to intercellular genomic variation in the normal, AD and AT brain. Neural aneuploidy leading to altered cellular physiology may significantly contribute to the pathogenesis of neurodegenerative diseases. These data indicate neural aneuploidy to be a newly identified feature of neurodegenerative diseases, similar to other devastative disorders hallmarked by aneuploidy such as chromosome syndromes and cancer.
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Enfermedad de Alzheimer/patología , Aneuploidia , Ataxia Telangiectasia/patología , Corteza Cerebral/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Niño , Aberraciones Cromosómicas/estadística & datos numéricos , Mapeo Cromosómico/métodos , Cromosomas/genética , Cromosomas/metabolismo , Cromosomas/ultraestructura , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 21/metabolismo , Cromosomas Humanos Par 21/ultraestructura , Femenino , Marcadores Genéticos/genética , Humanos , Masculino , Persona de Mediana Edad , Mosaicismo/estadística & datos numéricos , Neuronas/metabolismo , Neuronas/patología , Adulto JovenRESUMEN
Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer's disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex. Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review.
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Síndrome de Down/genética , Trisomía , Animales , Cromosomas Humanos Par 21 , Dosificación de Gen , Regulación de la Expresión Génica , Variación Genética , Humanos , Ratones , Ratones Transgénicos , MicroARNs/genética , Modelos Animales , Mosaicismo/estadística & datos numéricos , Proteoma/análisis , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: To investigate the effects of parental mosaicism on their preimplantation embryos. DESIGN: Case series. SETTING: An institute for reproductive and stem cell engineering. PATIENT(S): Sixty-eight mosaic couples. INTERVENTION(S): Assisted reproduction with preimplantation genetic testing (PGT). MAIN OUTCOME MEASURE(S): Karyotypes, embryo-related chromosomal abnormalities, and PGT results. RESULT(S): A total of 209 embryos were obtained from 68 mosaic couples, and 153 (73.21%) of 209 of the total embryos were obtained from 55 mosaic couples with abnormal sex chromosome numbers. Of these 153 embryos, 2 (1.31%) had an abnormal copy number of X chromosome, 1 had mosaicism with 46,XN,+X(mosaic, 40%), 1 (0.65%) had an extra Y chromosome, 3 (1.96%) exhibited both X chromosomal and autosomal abnormalities, and 4 (2.61%) exhibited de novo X chromosome structural abnormalities. A total of 56 (26.79%) of 209 embryos were obtained from mosaic couples (n = 13) with abnormal autosomal structures. Notably, of these 56 embryos, 5 (8.93%) had a 16q21-q24.3 copy number abnormality related to the parental karyotype, with a fragile site at 16q22; 5 (7.14%) exhibited 46,XX,dup(8p23.1-8p11.21) and 46,XY,del(8p22-8p11.21), which were related to the parental karyotype; and 10 (17.86%) were de novo chromosome abnormalities. CONCLUSION(S): Our data demonstrate that the risk of embryo-related chromosome abnormalities in mosaic patients with abnormal sex chromosomes is very low. Therefore, PGT may not need to be recommended for mosaic patients with abnormal copy numbers of sex chromosomes, especially for patients with financial difficulties. By contrast, the mosaic patients with structural abnormalities of autosomes may have a relatively high risk of abnormal embryos with an unbalanced segment of the involved chromosomes. Thus, PGT is highly recommended for mosaic patients with autosomal structure abnormalities, especially those with a fragile site at 16q22.
Asunto(s)
Fertilización In Vitro , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mosaicismo , Diagnóstico Preimplantación/métodos , Adulto , Blastocisto , Aberraciones Cromosómicas/embriología , Aberraciones Cromosómicas/estadística & datos numéricos , Análisis Citogenético/métodos , Análisis Citogenético/estadística & datos numéricos , Femenino , Fertilización In Vitro/métodos , Fertilización In Vitro/estadística & datos numéricos , Pruebas Genéticas/métodos , Humanos , Masculino , Mosaicismo/estadística & datos numéricos , Diagnóstico Preimplantación/estadística & datos numéricos , Estudios Retrospectivos , Factores de RiesgoAsunto(s)
Trastornos de los Cromosomas/complicaciones , Mosaicismo , Diagnóstico Prenatal , Niño , Preescolar , Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/epidemiología , Duplicación Cromosómica , Cromosomas Humanos Par 4 , Hibridación Genómica Comparativa , Femenino , Marcadores Genéticos , Humanos , Lactante , Recién Nacido , Masculino , Mosaicismo/estadística & datos numéricos , Embarazo , Diagnóstico Prenatal/estadística & datos numéricosRESUMEN
BACKGROUND & OBJECTIVE: Chromosome aneuploidy plays an important role in infertility, early pregnancy wastage and perinatal mortality. Cytogenetic & fluorescent in situ hybridization (FISH) studies on developmentally arrested and morphologically poor embryo have shown high frequency of chromosomal abnormality and mosaicism. In this study, we attempted to evaluate chromosome aneuploidy and mosaicism on human embryos through the use of FISH. METHODS: Sixty one grade IV un-transferable embryos were obtained from 25 patients undergoing in vitro fertilization (IVF). Forty six embryos were studied by FISH; 15 were lost during transport and handling. FISH probes (non-commercial) for centromeres of chromosome X, Y, 1 and 18 were used for the study. Zona of embryos were dissolved in 0.01N HCl containing 0.1 per cent Tween 20 for 2-3 min. RESULTS: Interpretable FISH results were obtained in 24 embryos. Nineteen embryos (79.2%) were disomic (normal) for chromosome X/Y or 1/18 and five (20.8%) were abnormal. Among five abnormal embryos two were triploidy (from same patient), one was double mosaic aneuploidy, one was mosaic aneuploidy and one was trisomy for sex chromosome (XXY). There was eleven embryos with presence of Y chromosome i.e., male and three embryos were female. INTERPRETATION & CONCLUSION: Skewing of sex ratio (11M vs. 3F) and low chromosome aneuploidy were observed in this preliminary study, however, it will be premature to conclude as the numbers of embryos studied were limited and so were the numbers of FISH probes used.
Asunto(s)
Aneuploidia , Fertilización In Vitro/estadística & datos numéricos , Hibridación Fluorescente in Situ , Mosaicismo/estadística & datos numéricos , Diagnóstico Preimplantación/métodos , Femenino , Humanos , Masculino , Proyectos Piloto , Embarazo , Preselección del Sexo , Obtención de Tejidos y ÓrganosRESUMEN
BACKGROUND: Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear. OBJECTIVE: We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY. METHODS: We analyzed baseline (1989-1993) blood samples from 933 men ≥65â¯years of age from the prospective Cardiovascular Health Study. Particulate matter ≤10⯵m (PM10), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse-distance weighted air monitor data were used to estimate each participants' monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR. RESULTS: Increased PM10 was associated with mLOY, namely decreased mLRR (p-trendâ¯=â¯0.03). Compared with the lowest tertile (≤28.5⯵g/m3), the middle (28.5-31.0⯵g/m3; ßâ¯=â¯-0.0044, pâ¯=â¯0.09) and highest (≥31⯵g/m3; ßâ¯=â¯-0.0054, pâ¯=â¯0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (ßâ¯=â¯-0.00035, pâ¯=â¯0.06) and smoking pack-years (ßâ¯=â¯-0.00011, pâ¯=â¯1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants. CONCLUSIONS: PM10 may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted.
Asunto(s)
Contaminantes Atmosféricos/análisis , Contaminación del Aire/estadística & datos numéricos , Cromosomas Humanos Y , Mosaicismo/estadística & datos numéricos , Aberraciones Cromosómicas Sexuales/estadística & datos numéricos , Anciano , Humanos , Masculino , Estudios ProspectivosRESUMEN
OBJECTIVE: To present the calculated frequencies, male to female sex-ratio, and modes of ascertainments in different levels of chromosomal mosaicism (CM) detected at amniocentesis. MATERIALS AND METHODS: This's a 10-years retrospective study between January 2008 and December 2017 and there were 13,752 cases of amniocentesis performed in MacKay Memorial Hospital, Taipei, Taiwan. Eight hundred and thirty four cases of CM were collected in this study. We reviewed their types of chromosomal abnormalities of mosaicism, the modes of ascertainment (including: advanced maternal age, abnormal ultrasound findings, abnormal maternal serum screening result, and other reasons), maternal age, gestational age at amniocentesis, fetal gender, and perinatal findings. After amniocentesis, in situ culture was performed and the results of karyotype with CM were divided in to three levels. RESULTS: In our sample of 13,752 amniocentesis, 834 cases with all levels of CM were collected in this study. Of them, there were 562 cases (4.09%) with level I mosaicism, 207 cases (1.51%) of level II mosaicism, and 65 cases (0.47%) of level III mosaicism (Table 1). In the group of advanced of maternal age (AMA), their calculated frequencies, 4.18% in level I, 1.46% in level II and 0.41% in level III, were very similar to those in total cases (p value = 0.206) without statistical significance. In the group of abnormal ultrasound findings, the calculated frequency was much higher in level III (0.87%), however, there was no statistical significance because of the small numbers of level III. In our cases of amniocentesis, the case numbers of male case (50.20%) is very similar to female (49.80%), and the male to female ratio was 1.01. But, we found more cases of male with CM (444 cases) than female (390 cases). The sex-ratio in different levels' calculated frequencies of CM showed similar in level I, and male prevalence was found in level II and III with statistical significance (p value = 0.022). The male prevalence also revealed in both numerical and structural abnormalities in level II and level III, but no difference in the cases of level I. CONCLUSION: In conclusion, our observation showed a novel finding of higher male prevalence of CM in level II and III, and both in numerical and structural abnormalities. It's consistent with the theory of better survival in male embryo after partial self-correction of initial chromosomal aberrations, male-specific selection against chromosomal abnormalities.