Figure 1 - uploaded by Gonzalo Arboleda
Content may be subject to copyright.
Ideogram of chromosome 21 with intervals according to STR markers used. PI (proximal interval), MI (medial interval), DI (distal interval), Tel (telomere), Cen (centromere).
Source publication
Free trisomy 21 is responsible for 95% of Down syndrome cases. Advanced maternal age and susceptible recombination patterns are recognized risk factors associated to Down syndrome. Maternal origin of trisomy occurs in approximately 90% of cases; paternal and mitotic origin share the remaining 10%. However, the recombination events that serve as a r...
Contexts in source publication
Context 1
... microsatellite polymorphisms of chromosome 21 were isolated using PCR amplification and separated by PAGE (polyacrylamide gel electrophoresis). The set of microsatellites, arrayed between the centromere and telomere of the long arm of chromosome 21, included: D21S1432, D21S11, D21S1437, APP Intron 7, D21S1411, and PFKL (Figure 1). ...
Similar publications
Conventional karyotyping for antenatal diagnosis is time consuming and hence there has been a growing interest in more rapid techniques for detection of chromosomal aneuploidies. Around 95% of Down syndrome cases are due to free trisomy 21.
The aims of this study were to demonstrate sensitivity of DNA diagnosis of Down syndrome using polymerase cha...
Eukaryotic genomes are organised into complex higher-order structures within the nucleus, and the three-dimensional arrangement of chromosomes is functionally important for global gene regulation. The existence of supernumerary chromosome 21 in Down syndrome may perturb the nuclear architecture at different levels, which is normally optimised to ma...
Meiotic recombination is generally suppressed across the centromere of eukaryotic chromosomes. In human, megabase-long satellite sequences and contiguous segmental duplications hamper both physical and fine scale genetic mapping in regions flanking centromeric DNA. We have developed polymorphic microsatellite markers embedded within the duplicated...
The hypothesis of a predisposition to meiotic nondisjunction for chromosome 21 carrying a specific molecular haplotype has been tested. The haplotype in question is defined by the restriction fragment length polymorphisms for the D21S1/D21S11 loci. Our results obtained on a sample of Northern Italian families with the occurrence of trisomy 21 (Down...
Citations
... A remarkable fact is that the frequency of DS is much higher at conception, given that up to 75% and 50% of DS fetuses identified during the first and second trimester, respectively, are lost before term [3,4]. There is strong evidence that most of the errors that lead to the trisomic condition are generated during meiotic processes, in which approximately 90% of the cases involving a 21 chromosome from maternal origin [5,6]. ...
Background:
Although Down syndrome (DS) is the most frequent human chromosomal disorder and it causes mainly intellectual disability, its clinical presentation is complex and variable.
Objective:
We aimed to analyze and compare the transcriptome disruption in several brain areas from individuals with DS and euploid controls as a new approach to consider a global systemic differential disruption of gene expression beyond chromosome 21.
Methods:
We used data from a DNA microarray experiment with ID GSE59630 previously deposited in the GEO DataSet of NCBI database. The array contained log2 values of 17,537 human genes expressed in several aeras of the human brain. We calculated the differential gene expression (Z-ratio) of all genes.
Results:
We found several differences in gene expression along the DS brain transcriptome, not only in the genes located at chromosome 21 but in other chromosomes. Moreover, we registered the lowest Z-ratio correlation between the age ranks of 16-22 weeks of gestation and 39-42 years (R2 = 0.06) and the highest Z-ratio correlation between the age ranks of 30-39 years and 40-42 years (R2 = 0.89). The analysis per brain areas showed that the hippocampus and the cerebellar cortex had the most different gene expression pattern when compared to the brain as a whole.
Conclusions:
Our results support the hypothesis of a systemic imbalance of brain protein homeostasis, or proteostasis network of cognitive and neuroplasticity process, as new model to explain the important effect on the neurophenotype of trisomy that occur not only in the loci of chromosome 21 but also in genes located in other chromosomes.
... A remarkable fact is that frequency of DS is much higher at conception, given that up to 75% and 50% of DS fetuses identi ed during the rst and second trimester, respectively, are lost before term [3,4]. There is strong evidence that most of the errors that lead to the trisomic condition are generated during meiotic processes, in which approximately 90% of the cases involving a 21 chromosome from maternal origin [5,6]. ...
Background: Although Down syndrome (DS) is a trisomy of chromosome 21 being the most frequent human chromosomal disorder mainly associated with variable levels of intellectual disability and other dysfunctions, the only dose disbalance effect would not enough to explain its genetic and functional complexity neurophenotype. In this context, we aimed to analyze and compare the disruption of transcriptome of several brain areas from individuals with DS and euploid controls as a new approach to consider a global systemic differential disruption of gene expression beyond of chromosome 21.
Methodology: To perform the analysis carried out in the present study, we used data from a DNA microarray experiment with ID GSE59630 previously deposited in the GEO DataSet of NCBI database. The array contained log2 values of 17,537 human genes expressed in several aeras of human brain. The data was collected from 58 postmortem brain samples of individuals with DS and 58 samples from euploid controls. We calculated the differential gene expression (Z-ratio) of all genes from the microarray according to the several brain areas, gene distribution per chromosome and age ranks.
Results: We found several differences in gene expression along the DS brain transcriptome, not only in the genes located at chromosome 21 but in other chromosomes. Moreover, we registered the lowest Z-ratio correlation between the age ranks of 16-22 weeks of gestation and 39-42 years (R²=0.06) and the highest Z-ratio correlation between the age ranks of 30-39 years and 40-42 years (R²=0.89). The analysis per brain areas showed that the hippocampus and the cerebellar cortex had the most different gene expression pattern when compared to the brain as a whole.
Conclusions: Our results revealed the complexity of gene expression networks in the transcriptome profiles of hippocampus, dorsolateral prefrontal cortex (DFC) and cerebellar cortex (CBC). Moreover, our approach opens a new vision of the genomic complexity of DS as a pathology of multiple and complex variables that are playing altogether to modeling their pathogenesis.
... If parental heterozygosity was retained in the trisomic offspring, non-disjunction error from meiosis I was considered. If parental heterozygosity was reduced to homozygosity, non-disjunction error from meiosis II was considered (20). When the two types existed at the same time, non-disjunction error from the parental chromosome exchange was considered. ...
... those associated with Klinefelter's syndrome) are usually from the father (41). The present study indicated that 85.4% of the cases of trisomy 21 had a maternal and 9.1% a paternal source, while the source was unknown for 5.5% (the selected markers were present in the mother and father, and the exact source remained undetermined), as supported by previous studies (20,42). Studies suggested that 5-9% of trisomy 21 cases result from paternal meiosis errors (43,44). ...
Quantitative fluorescence polymerase chain reaction (QF-PCR) may be used as a mid-pregnancy test to confirm the diagnosis of common fetal aneuploidies, but its use is controversial. The present study aimed to determine the value of QF-PCR for diagnostic confirmation of karyotyping and the impact of parental origin and meiosis stage on the detected aneuploidy. The present prospective cohort study included pregnant women (age, 21-45 years; gestational age, 17-25 weeks) who consulted between May 2015 and December 2016. Women were screened and only consecutive high-risk individuals were included (n=428). QF-PCR analysis of amniocytes was performed. Karyotype analysis was considered the gold standard. Parental karyotyping was performed if the embryo exhibited any aneuploidy. GeneMapper 3.2 was used for data analysis. There were no false-negative or false-positive QF-PCR results, with 100% concordance with the karyotype. The aneuploidy distribution (n=105) was 68.6% for trisomy 21, 19.0% for trisomy 18, 7.6% for sex chromosome aneuploidy, 3.8% for trisomy 13 and 1.0% for 48,XXX,+18. Regarding trisomy 21, most cases (86.1%) were of maternal origin, 8.3% paternal and 6.5% undefined. Trisomy 18 was 88.2% maternal and 11.8% paternal. Maternal meiosis stage errors in trisomy 21 mainly occurred in meiosis I, while the origin of trisomy 18 exhibited similar proportions between meiosis I and II. The combination of non-invasive pre-natal testing and QF-PCR may become a rapid and effective method for fetal aneuploidy detection. QF-PCR may provide more genetic information for clinical diagnosis and treatment than karyotyping alone.
... Dentro de las no disyunciones maternas, 80% ocurrió por errores en la MI. Estos hallazgos muestran una distribución similar a los reportes previos de la literatura (27,28). ...
... La frecuencia de eventos no disyuncionales en MI va aumentando en forma directamente proporcional a la edad materna, mientras los eventos en MII son más frecuentes en las mujeres menores de 25 años y en las mayores de 40 años. A pesar de que estas diferencias no son significativas, esta tendencia ha sido reportada en otros trabajos (28,31). ...
Down Syndrome (DS) is the most common trisomy in human beings. Its incidence is estimated in one of 745 live births. On a global scale, it is the most frequent cause of mental retardation. The origin of this trisomy is due to a meiotic non-disjunction in about 95% of cases and is usually maternal, especially in women above 35 years of age. The remaining 5% is due to errors in post-zygotic mitosis. Objective: identify the parental origin of the extra chromosome 21, when the error is not disyuncional and establish a correlation between these events and phenotypic manifestations of the patients affected. Materials and methods: we studied fifty families with a child with DS, using 5 STRs markers along 21q which allowed identification of the origin of chromosome 21 additional parents, the time when the error occurred and recombination presents. The statistical analysis was done using the package SPSS version 15.0 for Windows. Results: in 80% of households in the error was meiosis I and 20% in meiosis II, 98% of the additional chromosomes was home maternal and paternal 2% similar to those reported by other authors, correlation was found genotype-phenotype characteristics studied at 8, neck short and wide, third fontanel, prominent lower lip, palate narrow and short, crossing hélix root of the shell, alopecia, single palm crease and other anomalies as nevi and xeroderma and recombination events in 24,5% of the families tested. Conclusions: the maternal age and variation in the number of recombination is not associated with disjunctions meiotics I and II genotype phenotype correlation was found, but the sample size should be expanded in order to establish with certainty that the correlations.
... We confirmed the elevated maternal meiosis-I to meiosis-II error ratios as reported earlier by other investigators (Sherman et al., 1991;Ramírez et al., 2007). Although we observed increased paternal meiosis-I errors in our sample, in contrast to previous reports of increased nondisjunction in paternal meiosis-II (Savage et al., 1998;Oliver et al., 2009), it is important to note that chromosome 21, which has one chaisma, is generally more prone to nondisjunction in normal males (Soares et al., 2001). ...
Aim:
We wished to identify markers associated with allelic nondisjunction in nuclear families with Down syndrome (DS) offspring. Since the GRIK1 and GARS-AIRS-GART genes, mapping to chromosome 21q22.1, may be informative in this regard, we genotyped four single-nucleotide polymorphisms [30952599(A/G) rs363484; 30924733(A/G) rs363506; 34901423(A/G) rs2834235; 34877070(A/G) rs7283354] present in these genes using the SNaPshot(™) assay protocol.
Results:
We have reported 30952599(A/G)-rs363484 to be monomorphic in our sample population. Genotyping revealed 35/65 families to be informative for 34877070(A/G)-rs7283354 (GARS-AIRS-GART), whereas only 25/65 and 11/65 are informative for 34901423(A/G)-rs2834235 (GARS-AIRS-GART) and 30924733(A/G)-rs363506 (GRIK1) polymorphisms, respectively. The parent- and stage-of-origin of nondisjunction could be traced in 48/65 families using at least one polymorphic marker. A single trio provided internal validation for assignment of the parent- and stage-of-origin of nondisjunction whereby the nondisjoining alleles were independently identified as G-rs363506, G-rs2834235, and G-rs7283354, respectively. An enhanced ratio of meiosis-I to meiosis-II errors during maternal or paternal meioses accounts for allelic nondisjunction.
Conclusions:
The SNaPshot assay is quantitative and permits multiplexing for detection of allelic nondisjunction. Inclusion of additional informative chromosome 21-specific markers may aid rapid aneuploidy detection, screening, and prenatal counseling of parents at risk of having babies with DS.
... The vast majority of trisomy 21 was of maternal origin (93%), followed by paternal (5%) and mitotic origin (2%). Our findings confirm the model for DS origin found in other populations (Antonarakis, 1991;Gó mez et al., 2000;Petersen and Mikkelsen, 2000;Machatkova et al., 2005;Freeman et al., 2007;Ramírez et al., 2007;Ghosh et al., 2010). The obtained frequencies of maternal MIderived (86%) and MII-derived (14%) trisomy 21 were different from the study reported by Freeman et al. (2007), but similar to the studies on Mediterranean and Eastern Europe populations (Gó mez et al., 2000;Machatkova et al., 2005). ...
The aims of the present study were to assess (1) the parental origin of trisomy 21 and the stage in which nondisjunction occurs and (2) the relationship between altered genetic recombination and maternal age as risk factors for trisomy 21. The study included 102 cases with Down syndrome from the Croatian population. Genotyping analyses were performed by polymerase chain reaction using 11 short tandem repeat markers along chromosome 21q. The vast majority of trisomy 21 was of maternal origin (93%), followed by paternal (5%) and mitotic origin (2%). The frequencies of maternal meiotic I (MI) and meiotic II errors were 86% and 14%, respectively. The highest proportion of cases with zero recombination was observed among those with maternal MI derived trisomy 21. A higher proportion of telomeric exchanges were presented in cases with maternal MI errors and cases with young mothers, although these findings were not statistically significant. The present study is the first report examining parental origin and altered genetic recombination as a risk factor for trisomy 21 in a Croatian population. The results support that trisomy 21 has a universal genetic etiology across different human populations.
... Il est bien connu et abondamment étudié et rapporté aux Etats-Unis et en Europe. Il est cependant rarement rapporté dans les pays en voie de développement [9][10][11][12][13]. Cette rareté est probablement en rapport avec la disponibilité de connaissances et ou de compétences dans la génétique clinique et chromosomique. ...
... No disjunction doesn't only relate with maternal conditions, but also with paternal and mitotic conditions. A study verified that trisomy 21 was 90.9% maternal, 4.5% paternal and 4.5% from a mitotic origin; similar to distributions reported previously (4). It also confirmed that nondisjunction doesn't only take place in meiosis II but also in meiosis I (MI: 46.1%, MII: 53.9%).Even though it was established by other studies that MI is 70% and MII is 30% related to Down syndrome, it was reported that what causes it in 88% of cases is the extra copy of chromosome 21 derived from the mother, in 8% of the cases the father provided the extra copy of chromosome 21 and in the remaining 2% Down syndrome is due to mitotic errors; an error in cell division which occurs after fertilization when the sperm and ovum are joined (10). ...
Nondisjunction is the failure of homologous chromosomes to disjoin correctly during meiosis. This results in the production of gametes containing a greater or lesser chromosomal amount than normal ones. Consequently the individual may develop a trisomal or monosomal syndrome. Non disjunction can occur in both Meiosis I and Meiosis II of the cellular division. It is a cause of several abnormal medical conditions, including Down´s syndrome (trisomy of chromosome 21), Patau´s Syndrome (trisomy of chromosome 13), Edward´s Syndrome (trisomy of chromosome 18) and Turner´s Syndrome (the presence of only one X chromosome). It is also the main cause of many genetic disorders, however its origin and process remains vague. Although it results in the majority of cases from errors in the maternal meiosis II, both paternal and maternal meiosis I do influence it. The maternal age, is considered a risk factor of trisomies, as well as recombination alterations and many others that can affect the chromosomal segregation, such as genotoxicity and chromosomaltranslocations. We will review the results of previously realized studies between the years 2003 and 2009, found in ISI WEB, PUBMED, SCIENCE DIRECT,SPRINGER LINK and SCIELO, that led to important conclusions and highlighted interesting factors that can be the starting point to future investigation.//La no segregación es el fracaso de los cromosomas homólogos en separarse correctamente durante la meiosis. Esto resulta en la producción de gametos que contienen una cantidad de cromosomas mayor o menor a la encontrada en una célula normal. Consecuentemente, el individuo puede desarrollar una trisomía o monosomía. La no disyunción puede ocurrir en meiosis I o meiosis II de la división celular, es una causa de diversas condiciones médicas anormales, incluyendo el Síndrome de Down (trisomía del cromosoma 21), Síndrome de Patau (trisomía del cromosoma 13), Síndrome de Edward (trisomía del cromosoma 18) y Síndrome de Turner (la presencia de un solo cromosoma X). A pesar de que es la causa de numerosos trastornos genéticos, aún no se conoce su etiología exacta y el proceso en el cual se lleva a cabo. La no disyunción se origina en el mayor de los casos de errores en la meiosis II materna, sin embargo, la meiosis paterna y la meiosis I materna influyen en ella. La edad materna se considera como un factor de riesgo de las trisomías, igual que la alteración de la recombinación y otros factores que pueden afectar la segregación cromosómica, tal como la genotoxicidad y translocaciones cromosómicas. Esta revisión se realizará con base en artículos publicados entre 2003 y 2009 en ISI Web, Science Direct, PUBMED, SPRINGER y SCIELO; se interpretará y analizará en ella los resultados de estos estudios que lograron demostrar conclusiones importantes y sobresaltaron factores interesantes que pueden ser el punto de partida para próximas investigaciones.
... In addition, trisomy 21 is a major cause of premature pregnancy failure. It is estimated that 1/150 conceptions have trisomy 21 and that 80% of these are lost during early pregnancy (Boué et al., 1975;Hassold and Jacobs, 1984;Freeman et al., 1991); The nondisjunction event that results in two copies of chromosome 21 takes place in anaphase of meiosis I during oocyte maturation before ovulation, and/or in anaphase of meiosis II around the time of fertilization in the adult female (Ramírez et al., 2007). ...
To explore the relationship between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), the central enzymes in folate metabolism that affects DNA methylation and synthesis, and the risk of Down syndrome in China.
Genomic DNA was isolated from the peripheral lymphocytes of 64 mothers of children with Down syndrome and 70 age matched control subjects. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFR 677C-->T, MTRR 66A-->G and the relationship between these genotypes and the risk of Down syndrome was analyzed.
The results show that the MTHFR 677C-->T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 3.78 (95% confidence interval (CI), 1.78 approximately 8.47). In addition, the homozygous MTRR 66A-->G polymorphism was independently associated with a 5.2-fold increase in estimated risk (95% CI, 1.90 approximately 14.22). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than the presence of either alone, with an odds ratio of 6.0 (95% CI, 2.058 approximately 17.496). The two polymorphisms appear to act without a multiplicative interaction.
MTHFR and MTRR gene mutation alleles are related to Down syndrome, and CT, TT and GG gene mutation types increase the risk of Down syndrome.
Background
Although Down syndrome (DS) is a trisomy of chromosome 21 being the most frequent human chromosomal disorder mainly associated with variables dysfunctions.
Objective
In this context, we aimed to analyze and compare the disruption of transcriptome of several brain areas from individuals with DS and euploid controls as a new approach to consider a global systemic differential disruption of gene expression beyond of chromosome 21.
Methods
We used data from a DNA microarray experiment with ID GSE59630 previously deposited in the GEO DataSet of NCBI database. The array contained log2 values of 17,537 human genes expressed in several aeras of human brain. We calculated the differential gene expression (Z-ratio) of all genes.
Results
We found several differences in gene expression along the DS brain transcriptome, not only in the genes located at chromosome 21 but in other chromosomes. Moreover, we registered the lowest Z-ratio correlation between the age ranks of 16–22 weeks of gestation and 39–42 years (R 2 = 0.06) and the highest Z-ratio correlation between the age ranks of 30–39 years and 40–42 years (R 2 = 0.89). The analysis per brain areas showed that the hippocampus and the cerebellar cortex had the most different gene expression pattern when compared to the brain as a whole.
Conclusions
Our results support the hypothesis of a systemic imbalance of brain protein homeostasis, or proteostasis network of cognitive and neuroplasticity process as new model to explain the important effect on the neurophenotype of trisomy that occur not only in loci of chromosome 21 but also in genes located in other chromosomes.
