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1.
Gene ; 764: 145099, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32861879

RESUMO

Down syndrome (DS, trisomy 21) is the most common major chromosomal aneuploidy compatible with life. The additional whole or partial copy of chromosome 21 results in genome-wide imbalances that drive the complex pathobiology of DS. Differential DNA methylation in the context of trisomy 21 may contribute to the variable architecture of the DS phenotype. The goal of this study was to examine the genomic DNA methylation landscape in myocardial tissue from non-fetal individuals with DS. >480,000 unique CpG sites were interrogated in myocardial DNA samples from individuals with (n = 12) and without DS (n = 12) using DNA methylation arrays. A total of 93 highly differentially methylated CpG sites and 16 differentially methylated regions were identified in myocardial DNA from subjects with DS. There were 18 differentially methylated CpG sites in chromosome 21, including 5 highly differentially methylated sites. A CpG site in the RUNX1 locus was differentially methylated in DS myocardium, and linear regression suggests that donors' age, gender, DS status, and RUNX1 methylation may contribute up to ~51% of the variability in RUNX1 mRNA expression. In DS myocardium, only 58% of the genes overlapping with differentially methylated regions codify for proteins with known functions and 24% are non-coding RNAs. This study provides an initial snapshot on the extent of genome-wide differential methylation in myocardial tissue from persons with DS.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Síndrome de Down/genética , Epigênese Genética , Miocárdio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Cromossomos Humanos Par 21/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Epigenômica , Feminino , Loci Gênicos/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Adulto Jovem
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(7): 747-750, 2020 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-32619256

RESUMO

OBJECTIVE: To study the correlation of genome-wide distribution of 6-methyladenine (6mA) of DNA in chorionic tissues from abortuses with monosomy 21. METHODS: Genomic DNA was extracted from chorionic samples from four abortuses with monosomy 21 and four without. After quality and purity test, partial DNA was subjected to chromatin immunoprecipitation with anti-6mA antibody, and then identified by sequencing. The sequencing data was analyzed by using bioinformatic software for the difference in 6mA between the two groups. RESULTS: Analysis of read peaks suggested that the control group have much more 6mA genes (n=4607) compared with the experiment group (n=1059). For chromosome 21, this difference is even more pronounced (8032 vs. 1769). Above results suggested that the level of 6mA modification in monosomy 21 is low. Gene ontology enrichment analysis and KEGG pathway enrichment analysis indicated that the absence of 6mA genes in monosomy 21 is closely related to the growth and development of embryo. CONCLUSION: The 6mA modification of human genes may play a similar role to 5-methylcytosine (5mC) modification during the growth and development of embryos.


Assuntos
Feto Abortado , Cromossomos Humanos Par 21 , Metilação de DNA , Adenina/análogos & derivados , Cromossomos Humanos Par 21/genética , DNA , Humanos , Monossomia
4.
Hum Genet ; 139(12): 1555-1563, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32535809

RESUMO

The chromosomal region critical in Down syndrome has long been analyzed through genotype-phenotype correlation studies using data from many patients with partial trisomy 21. Owing to that, a relatively small region of human chromosome 21 (35.9 ~ 38.0 Mb) has been considered as Down syndrome critical region (DSCR). In this study, microarray-based comparative genomic hybridization analysis identified complex rearrangements of chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome. Although the patient did not show up-slanting palpebral fissures and single transverse palmar creases, other symptoms were consistent with Down syndrome. Rearrangements were analyzed by whole-genome sequencing using Nanopore long-read sequencing. The analysis revealed that chromosome 21 was fragmented into seven segments and reassembled by six connected points. Among 12 breakpoints, 5 are located within the short region and overlapped with repeated segments. The rearrangement resulted in a maximum gain of five copies, but no region showed loss of genomic copy numbers. Breakpoint-junctions showed no homologous region. Based on these findings, chromoanasynthesis was considered as the mechanism. Although the distal 21q22.13 region was not included in the aberrant regions, some of the genes located on the duplicated regions, SOD1, SON, ITSN1, RCAN1, and RUNX1, were considered as possible candidate genes for clinical features of the patient. We discussed the critical region for Down syndrome, with the literature review.


Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos/genética , Síndrome de Down/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa/métodos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/genética , Síndrome de Down/fisiopatologia , Feminino , Dosagem de Genes/genética , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente/métodos , Lactente , Análise em Microsséries/métodos , Antígenos de Histocompatibilidade Menor/genética , Proteínas Musculares/genética , Superóxido Dismutase-1/genética , Sequenciamento Completo do Genoma
5.
Artigo em Inglês | MEDLINE | ID: mdl-32365584

RESUMO

Partial deletion of chromosome 21q is a very rare genetic condition with highly variable phenotypic features including heart defects, high or cleft palate, brain malformations (e.g., cerebral atrophy), developmental delay and intellectual disability. So far, there is very limited knowledge about psychiatric disorders and their effective treatment in this special population. To fill this gap, the authors present the case of an initially five-year-old girl with distal deletion (del21q22.2) and comorbid oppositional defiant disorder (main psychiatric diagnosis) covering a period of time of almost four years comprising initial psychological/psychiatric assessment, subsequent treatment with Parent-Child Interaction Therapy (PCIT), and follow-up assessments. Post-intervention results including a 19-month follow-up indicated good overall efficacy of PCIT and high parental satisfaction with the treatment. This case report makes a substantial contribution to enhancing knowledge on psychiatric comorbidity and its effective treatment in patients with terminal 21q deletion. Moreover, it emphasizes the necessity of multidisciplinarity in diagnosis and treatment due to the variety of anomalies associated with 21q deletion. Regular screenings for psychiatric disorders and (if indicated) thorough psychological and psychiatric assessment seem to be reasonable in most affected children, as children with developmental delays are at increased risk of developing psychiatric disorders. As demonstrated with this case report, PCIT seems to be a good choice to effectively reduce disruptive behaviors in young children with partial deletion of chromosome 21q.


Assuntos
Transtornos de Deficit da Atenção e do Comportamento Disruptivo/genética , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/terapia , Deleção Cromossômica , Relações Pais-Filho , Pré-Escolar , Cromossomos Humanos Par 21/genética , Comorbidade , Feminino , Humanos , Resultado do Tratamento
6.
Pediatr Blood Cancer ; 67(4): e28188, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020774

RESUMO

BACKGROUND: Transient abnormal myelopoiesis (TAM) is a unique myeloproliferative disorder that occurs in neonates with constitutional trisomy 21/Down syndrome (DS). Although TAM also develops in neonates without constitutional trisomy 21, the clinical, cytogenetic, and molecular characteristics of those patients are not fully understood. PROCEDURE: We retrospectively evaluated the clinical and cytogenetic findings and GATA1 mutation status of 17 neonates with TAM and nonconstitutional trisomy 21 tested for GATA1 mutations at our institute, and compared the findings with those of 64 neonates with TAM and constitutional trisomy 21/DS. RESULTS: DS clinical features were observed in five of the 17 (29%) patients. In all patients, both trisomy 21 and GATA1 mutations were detected in diagnostic samples. Over a median follow-up of 33 (range, 0-139) months, early death (< 6 months of age) occurred in four patients (24%). Overall and event-free survivals were not significantly different between the patients with TAM and nonconstitutional trisomy 21 and those with TAM and constitutional trisomy 21/DS (five-year overall survival: 76% ± 10% vs 53% ± 13%, P = 0.40; five-year event-free survival: 55% ± 13% vs 48% ± 12%, P = 0.90). The five-year cumulative incidence of progression to myeloid leukemia of DS was also similar between the groups (21% vs 24%, P = 0.80). CONCLUSIONS: Patients with TAM and nonconstitutional trisomy 21 exhibited similar biology and outcomes to those with TAM and constitutional trisomy 21/DS. The possibility of TAM should be considered even in phenotypically normal neonates with TAM symptoms, for appropriate management.


Assuntos
Cromossomos Humanos Par 21/genética , Síndrome de Down , Fator de Transcrição GATA1/genética , Mutação , Mielopoese/genética , Intervalo Livre de Doença , Síndrome de Down/genética , Síndrome de Down/mortalidade , Síndrome de Down/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Taxa de Sobrevida
7.
Blood Cancer J ; 10(2): 16, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029705

RESUMO

Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.


Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/prevenção & controle , Proteínas de Fusão Oncogênica/metabolismo , Translocação Genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Biomarcadores Tumorais/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Fusão Oncogênica/genética , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rac de Ligação ao GTP/genética
8.
Taiwan J Obstet Gynecol ; 59(1): 157-161, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039787

RESUMO

OBJECTIVE: A prenatal diagnosis of partial monosomy 21q(21q22.1→ qter) in fetus with intrauterine growth restriction and corpus callosum dysgenesis but escaped from the detection by cell free DNA testing was reported. CASE REPORT: A 31-year-old, primigravida women, presented with intrauterine growth restriction and corpus callosum dysgenesis at 23 weeks of gestational age by anatomic ultrasound screening. The interphase fluorescence in situ hybridization (FISH) analysis on amniocytes revealed monosomy 21, while the cytogenetic analysis and array comparative genomic hybridization (CGH) with CytoScan gene chip ascertained a 12.35 Mb deletion at 21q22.1q22.3. CONCLUSION: Although noninvasive prenatal testing is used extensively and can be applied to certain microdeletion diseases, the application for uncommon deletion disorders such as the present case remains limited. Prenatal examination with detailed ultra-sonography combined with different modalities of invasive prenatal testing can provide a more comprehensive information.


Assuntos
Agenesia do Corpo Caloso/diagnóstico , Retardo do Crescimento Fetal/diagnóstico , Monossomia/diagnóstico , Diagnóstico Pré-Natal/métodos , Adulto , Agenesia do Corpo Caloso/embriologia , Agenesia do Corpo Caloso/genética , Cromossomos Humanos Par 21/genética , Hibridização Genômica Comparativa , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Hibridização in Situ Fluorescente , Monossomia/genética , Gravidez
9.
Cell Rep ; 30(4): 1152-1163.e4, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31995755

RESUMO

Altered neural dynamics in the medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder Down syndrome (DS). Here, we demonstrate non-overlapping behavioral differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial working memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, and Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice show slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, and increased modulation of hippocampal high gamma); Dp10Yey mice show impaired alternation performance and reduced theta modulation of hippocampal low gamma; and Dp17Yey mice are not significantly different from the wild type. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21.


Assuntos
Disfunção Cognitiva/fisiopatologia , Síndrome de Down/genética , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Memória de Curto Prazo/fisiologia , Memória Espacial/fisiologia , Trissomia/genética , Animais , Cromossomos Humanos Par 21/genética , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Eletroencefalografia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Ritmo Teta/genética , Trissomia/fisiopatologia
11.
Iran Biomed J ; 24(1): 60-3, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301695

RESUMO

Background: Mosaicism of a normal cell population and an unbalanced autosomal chromosome rearrangement is rarely seen. If the abnormal cell line contributes to a minor part of soma, the phenotype is expected to be normal. Case Report: We report a 29-year-old woman who had balance chromosomal translocation of 46,XX,t(5;21) with a two-year-old affected girl, characterized by mental retardation, dystrophia, hearing impartment, and dysphagia. Methods and Results: Cytogenetic investigation revealed a low mosaic unbalanced translocation of 46,XX,t(5;21)/ 46,XX, which was confirmed by fluorescence in situ hybridization analysis. Studying 200 metaphases and interphases of peripheral blood sample revealed 70% partial monosomy of 21q22 and partial trisomy of 5q(35.3) and 30% of normal pattern. Conclusion: In rare cases such as this study, parents with balanced translocation with no phenotypes may lead to a mosaic unbalanced translocation with abnormal phenotypes in offspring, which underscores the need for prenatal karyotyping and genetics counseling.


Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 5/genética , Citogenética , Hibridização in Situ Fluorescente , Mosaicismo , Translocação Genética/genética , Pré-Escolar , Humanos , Cariotipagem
12.
Cancer Genomics Proteomics ; 17(1): 41-48, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882550

RESUMO

BACKGROUND/AIM: The chromosome translocation t(14;21)(q11;q22) was reported in four pediatric T-cell lymphoblastic leukemias and was shown to activate the OLIG2 gene. MATERIALS AND METHODS: A pediatric T-cell lymphoblastic lymphoma was investigated using G-banding chromosome analysis, fluorescence in situ hybridization (FISH), and immunocytochemistry. RESULTS: The malignant cells carried a t(14;21)(q11;q22) aberration. The translocation moves the enhancer elements of TRA/TRD from band 14q11 to 21q22, a few thousands kbp downstream of OLIG1 and OLIG2, resulting in the production of both OLIG1 and OLIG2 proteins. CONCLUSION: The translocation t(14;21)(q11;q22) occurs in some pediatric T-cell lymphoblastic malignancies. Activation of both OLIG1 and OLIG2 by t(14;21)(q11;q22) in T-lymphoblasts and the ensuing deregulation of thousands of genes could explain the highly malignant disease and resistance to treatment that has characterized this small group of patients.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 21/genética , Proteínas do Tecido Nervoso/genética , Fator de Transcrição 2 de Oligodendrócitos/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Translocação Genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bandeamento Cromossômico , Evolução Fatal , Humanos , Hibridização in Situ Fluorescente , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Prognóstico
13.
Hum Genet ; 139(2): 215-226, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31848685

RESUMO

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.


Assuntos
Cromossomos Humanos Par 21/genética , Fenda Labial/genética , Fissura Palatina/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/métodos , Criança , Colômbia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino
14.
Medicina (Kaunas) ; 55(11)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703316

RESUMO

Background and Objective: Although Down syndrome is the most frequent aneuploidy, its pathogenic molecular mechanisms are not yet fully understood. The aim of our study is to quantify-by qRT-PCR-the expression levels of both the mature forms and the pri-miRNAs of the microRNAs resident on chromosome 21 (miR(21)) in the amniotic fluid samples from Down syndrome singleton pregnancies and to estimate the impact of the differentially expressed microRNAs on Down syndrome fetal heart and amniocytes transcriptomes. Materials and methods: We collected amniotic fluid samples harvested by trained obstetricians as part of the second trimester screening/diagnostic procedure for aneuploidies to assess the trisomy 21 status by QF-PCR and karyotyping. Next, we evaluated-by Taqman qRT-PCR-the expression levels of both the mature forms and the pri-miRNA precursors of the microRNAs resident on chromosome 21 in amniotic fluid samples from singleton Down syndrome and euploid pregnancies. Further, we combined miRWalk 3.0 microRNA target prediction with GEO DataSets analysis to estimate the impact of hsa-miR-99a abnormal expression on Down syndrome heart and amniocytes transcriptome. Results: We found a statistically significant up-regulation of the mature form of miR-99a, but not pri-miR-99a, in the amniotic fluid samples from Down syndrome pregnancies with female fetuses. GATHER functional enrichment analysis of miRWalk3.0-predicted targets from Down syndrome amniocytes and fetal hearts transcriptome GEODataSets outlined both focal adhesion and cytokine-cytokine receptor interaction signaling as novel signaling pathways impacted by miR-99a and associated with cardiac defects in female Down syndrome patients. Conclusions: The significant overexpression of miR-99a, but not pri-miR-99a, points towards an alteration of the post-transcriptional mechanisms of hsa-miR-99a maturation and/or stability in the female trisomic milieu, with a potential impact on signaling pathways important for proper development of the heart.


Assuntos
Líquido Amniótico/metabolismo , Síndrome de Down/genética , MicroRNAs/análise , Adulto , Cromossomos Humanos Par 21/genética , Síndrome de Down/metabolismo , Feminino , Humanos , Projetos Piloto , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/genética , Romênia , Regulação para Cima/fisiologia
15.
Taiwan J Obstet Gynecol ; 58(6): 869-871, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31759545

RESUMO

OBJECTIVE: We present a familial 21q22.3 microduplication in a fetus associated with prenatally detected congenital heart defects (CHD). CASE REPORT: A 38-year-old woman underwent amniocentesis at 22 weeks of gestation because of sonographic findings of double outlet of right ventricle, ventricular septal defect and transposition of great artery in the fetus. Her husband was 42 years old, and there was no CHD and congenital malformation in the family. Cytogenetic analysis revealed a karyotype of 46,XY in the fetus. Simultaneous array comparative genomic hybridization (aCGH) analysis using uncultured amniocytes revealed a 0.56-Mb microduplication of 21q22.3 or arr 21q22.3 (47,482,210-48,043,704)×3.0 [GRCh37 (hg19)] encompassing nine Online Mendelian Inheritance in Man (OMIM) genes of FTCD, SPATC1L, LSS, MCM3AP, YBEY, PCNT, DIP2A, S100B and PRMT2. aCGH analysis of the parental bloods revealed that the phenotypically normal father carried the same microduplication. The parents decided to continue the pregnancy, and a 3168-g male baby was delivered at term without Down syndrome phenotype except CHD. Mutational analysis of the CRELD1 gene on the DNA extracted from the cord blood showed no mutation in CRELD1. Postnatal molecular cytogenetic analysis of the cord blood confirmed the prenatal diagnosis. The infant underwent a successful heart surgery to correct the CHD and was doing well without psychomotor or developmental delay at six months of age. CONCLUSION: Prenatal diagnosis of 21q22.3 microduplication associated with CHD should include a differential diagnosis of Down syndrome.


Assuntos
Amniocentese/métodos , Transtornos Cromossômicos/diagnóstico , Duplicação Cromossômica/genética , Cromossomos Humanos Par 21/genética , Doenças Fetais/diagnóstico , Cardiopatias Congênitas/diagnóstico , Ultrassonografia Pré-Natal/métodos , Adulto , Transtornos Cromossômicos/genética , Feminino , Doenças Fetais/genética , Cardiopatias Congênitas/genética , Humanos , Cariótipo , Cariotipagem , Gravidez
16.
Nat Commun ; 10(1): 4766, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628327

RESUMO

Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.


Assuntos
Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Cinurenina/metabolismo , Receptores de Interferon/genética , Trissomia , Animais , Vias Biossintéticas/genética , Linhagem Celular , Citocinas/metabolismo , Síndrome de Down/metabolismo , Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Metabolômica/métodos , Camundongos Endogâmicos C57BL , Ácido Quinolínico/metabolismo , Receptores de Interferon/metabolismo
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 1031-1034, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598954

RESUMO

OBJECTIVE: To emphasize the clinical significance of copy number variations (CNVs) detection by describing a case misdiagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. METHODS: A girl with obesity and short stature was diagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. Considering the discrepancy of her karyotype with her phenotype, genomic CNVs was detected by next-generation sequencing and the result was verified by quantitative PCR (qPCR). RESULTS: A microduplication of 16p11.2: 29 642 339-29 775 631 (133.292 kb) was detected. qPCR assay for QPRT and SPN located in the duplicated region confirmed the finding of CNVs assay. Meanwhile, her parents did not present similar duplication in 16p11.2. CONCLUSION: The 16p11.2 microduplication was a novel genomic structural variation in the girl, though it may not be associated with her clinical manifestations. Chromosomal microarray or next-generation sequencing-based CNVs detection can accurately determine the origin of small supernumerary marker chromosome and reduce the chance of misdiagnosis.


Assuntos
Cromossomos Humanos Par 21/genética , Erros de Diagnóstico , Síndrome de Down , Cariotipagem , Trissomia/diagnóstico , Bandeamento Cromossômico , Variações do Número de Cópias de DNA , Feminino , Humanos
18.
J Appl Genet ; 60(3-4): 347-355, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31456164

RESUMO

Chromosome 21 abnormalities are the most frequent genetic findings in childhood B cell precursor acute lymphoblastic leukemia (BCP-ALL) cases. Majority of patients are effectively diagnosed with fluorescence in situ hybridization (FISH) and karyotyping; however, some cases may require additional tools to be used. Bone marrow samples of 373 childhood BCP-ALL patients were tested for chromosome 21 copy number variations (CNVs) with Multiplex Ligation-dependent Probe Amplification (MLPA) P327 array. Results from MLPA and cytogenetics were compared between groups according to the type of abnormality found on chromosome 21. Out the group of 235 patients, chromosome 21 multiplication was found by FISH assay in 56 cases (23.81%), ETV6-RUNX1 fusion in 34 (14.47%) and iAMP21 in 3 (1.28%) children, remaining 142 (60.43%) patients had no known chromosome 21 aberration. Median peak ratios of all tested probes in MLPA in aforementioned groups were 1.47 (IQR 1.28-1.77) vs. 1.00 (IQR 1.00-1.09) vs. 2.79 (IQR 1.97-2.83) vs. 1.00 (1.00-1.11), respectively. Aforementioned peak ratio of ETV6-RUNX1 fusion group was similar with patients of no known chromosome 21 aberration (p = 0.71). Interestingly, both groups differed from patients with chromosome 21 multiplication (p < 10-5) and with iAMP21 (p < 10-5). All cases of iAMP21 were correctly recognized by MLPA. MLPA seems to be good additional tool in the diagnostic process of chromosome 21 CNVs, especially in cases with iAMP21.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 21/genética , Variações do Número de Cópias de DNA/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Citodiagnóstico , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Translocação Genética/genética
19.
Cancer Sci ; 110(10): 3358-3367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385395

RESUMO

Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non-DS-ALL), those with DS and ALL (DS-ALL) harbor uncommon genetic alterations, suggesting DS-ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS-ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS-ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non-DS-ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome-like subtype, a high-risk B-cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS-ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS-ALL, but not non-DS-ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B-cell precursors might be associated with increased incidence of B-cell precursor ALL in DS patients.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Metilação de DNA , Síndrome de Down/complicações , Perfilação da Expressão Gênica/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Diferenciação Celular , Criança , Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Cromossomo Filadélfia , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Análise de Sequência de RNA
20.
Med Hypotheses ; 131: 109289, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443780

RESUMO

Mental retardation is a progressive condition in Down syndrome: intelligence starts to decline linearly within the first year. This phenomenon could be related to the overproduction of a toxic compound, hydrogen sulfide. Indeed, a gene located on chromosome 21 controls the production of cystathionine-ß-synthase, an enzyme involved in hydrogen sulfide production in the central nervous system. It has recently been demonstrated that excess cystathionine-ß-synthase levels are needed and sufficient to induce cognitive phenotypes in mouse models of Down syndrome. Thus, two therapeutic options might be used in Down syndrome patients: the use of a specific cystathionine ß-synthase inhibitor and the use of an effective antidote to reduce hydrogen sulfide toxicity. Prenatal treatment of Down syndrome fetuses is also suggested.


Assuntos
Cistationina beta-Sintase/fisiologia , Síndrome de Down/psicologia , Sulfeto de Hidrogênio/antagonistas & inibidores , Deficiência Intelectual/terapia , Ácido Amino-Oxiacético/uso terapêutico , Animais , Benserazida/uso terapêutico , Encéfalo/metabolismo , Cromossomos Humanos Par 21/genética , Cobamidas/uso terapêutico , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina beta-Sintase/genética , Modelos Animais de Doenças , Progressão da Doença , Dissulfiram/uso terapêutico , Síndrome de Down/genética , Inibidores Enzimáticos/uso terapêutico , Dosagem de Genes , Humanos , Sulfeto de Hidrogênio/metabolismo , Recém-Nascido , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Camundongos , Mitocôndrias/metabolismo , Ratos , Nitrito de Sódio/uso terapêutico , Especificidade da Espécie , Tiossulfatos/metabolismo
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