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1.
Rinsho Ketsueki ; 60(9): 1020-1026, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597823

RESUMO

Fifty years after its discovery, the enigma of monosomy 7 (-7) is eventually unraveling. The key to understanding -7 is "haploinsufficiency" mechanism, through which the function of myeloid tumor-suppressor genes is lost via the deletion/mutation of one allele. In this century, powerful tools such as microarray-CGH and next generation sequencing have enabled the search for tumor-suppressor genes on chromosome 7. Five genes (Samd9, Samd9-like (Samd9L), Ezh2, MLL3, and CUX1) have been identified and their myeloid tumor suppression potential has been verified using mouse models. Mice lacking one Samd9L gene developed MDS at an advanced age, whereas mice children harboring a gain-of-function mutation of Samd9 or Samd9L gene suffer from bone marrow failure, which is frequently followed by childhood MDS with -7, suggesting that these tumor-suppressor genes are the key to understanding not only MDS with -7 but also MDS in general. However, lack of Ezh2 and MLL3, which encode epigenetic regulators, contribute to the promotion of the progression of myeloid tumor cells that harbor abnormalities in the p53 or Ras pathways.


Assuntos
Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Animais , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Proteínas de Ligação a DNA , Proteína Potenciadora do Homólogo 2 de Zeste , Genes Supressores de Tumor , Proteínas de Homeodomínio , Humanos , Camundongos , Proteínas Nucleares , Proteínas , Proteínas Repressoras , Proteínas Supressoras de Tumor/genética
2.
Cancer Sci ; 110(10): 3132-3144, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31390121

RESUMO

Alternative splicing, regulated by DEAD-Box Helicase (DDX) families, plays an important role in cancer. However, the relationship between the DDX family and cancer has not been fully elucidated. In the present study, we identified a candidate oncogene DDX56 on Ch.7p by a bioinformatics approach using The Cancer Genome Atlas (TCGA) dataset of colorectal cancer (CRC). DDX56 expression was measured by RT-qPCR and immunochemical staining in 108 CRC patients. Clinicopathological and survival analyses were carried out using three CRC datasets. Biological roles of DDX56 were explored by gene set enrichment analysis (GSEA), and cell proliferation in vitro and in vivo, cell cycle assays, and using DDX56-knockdown or overexpressed CRC cells. RNA sequencing was carried out to elucidate the effect of DDX56 on mRNA splicing. We found that DDX56 expression was positively correlated with the amplification of DDX56 and was upregulated in CRC cells. High DDX56 expression was associated with lymphatic invasion and distant metastasis and was an independent poor prognostic factor. In vitro analysis, in vivo analysis and GSEA showed that DDX56 promoted proliferation ability through regulating the cell cycle. DDX56 knockdown reduced intron retention and tumor suppressor WEE1 expression, which functions as a G2-M DNA damage checkpoint. We have identified DDX56 as a novel oncogene and prognostic biomarker of CRC that promotes alternative splicing of WEE1.


Assuntos
Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/patologia , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Amplificação de Genes , Proteínas Nucleares/genética , Proteínas Tirosina Quinases/genética , Regulação para Cima , Idoso , Animais , Ciclo Celular , Linhagem Celular Tumoral , Cromossomos Humanos Par 7/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Transplante de Neoplasias , Prognóstico , Processamento de RNA , Análise de Sequência de RNA , Análise de Sobrevida
3.
BMC Bioinformatics ; 20(1): 431, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426747

RESUMO

BACKGROUND: Protein pulldown using Methyl-CpG binding domain (MBD) proteins followed by high-throughput sequencing is a common method to determine DNA methylation. Algorithms have been developed to estimate absolute methylation level from read coverage generated by affinity enrichment-based techniques, but the most accurate one for MBD-seq data requires additional data from an SssI-treated Control experiment. RESULTS: Using our previous characterizations of Methyl-CpG/MBD2 binding in the context of an MBD pulldown experiment, we build a model of expected MBD pulldown reads as drawn from SssI-treated DNA. We use the program BayMeth to evaluate the effectiveness of this model by substituting calculated SssI Control data for the observed SssI Control data. By comparing methylation predictions against those from an RRBS data set, we find that BayMeth run with our modeled SssI Control data performs better than BayMeth run with observed SssI Control data, on both 100 bp and 10 bp windows. Adapting the model to an external data set solely by changing the average fragment length, our calculated data still informs the BayMeth program to a similar level as observed data in predicting methylation state on a pulldown data set with matching WGBS estimates. CONCLUSION: In both internal and external MBD pulldown data sets tested in this study, BayMeth used with our modeled pulldown coverage performs better than BayMeth run without the inclusion of any estimate of SssI Control pulldown, and is comparable to - and in some cases better than - using observed SssI Control data with the BayMeth program. Thus, our MBD pulldown alignment model can improve methylation predictions without the need to perform additional control experiments.


Assuntos
Biologia Computacional/métodos , Metilação de DNA/genética , DNA-Citosina Metilases/metabolismo , DNA/metabolismo , Modelos Biológicos , Alinhamento de Sequência , Algoritmos , Pareamento de Bases , Cromossomos Humanos Par 7/genética , Ilhas de CpG/genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Domínio de Ligação a CpG Metilada , Análise de Sequência de DNA/métodos
4.
Rinsho Ketsueki ; 60(7): 800-809, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391370

RESUMO

In myeloid neoplasms, deletions of the long arm of chromosome 5 del(5q) and 7 (-7/del(7q) ) are common karyotypic abnormalities. The concurrence of del(5q) and -7/del(7q) accounts for poor prognosis in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Comprehensive analysis of copy number abnormalities and genetic mutations related to del(5q) and -7/del(7q) revealed previously cryptic pathophysiology, leading to frequent hemizygous/homozygous mutations and haploinsufficiency. In addition, detailed somatic mutations on chr5q were detected using whole-exome sequencing. CSNK1A1 and G3BP1 are located within the common deleted regions (CDRs) (5q31.1-5q33.1), and another driver gene DDX41 is present in the more telomeric region (5q35.3). All the genes mentioned above exhibited haploinsufficiency because of deletions, and low expression of G3BP1 and DDX41 correlated with poor survival. The related mutational events outside of chr5q, TP53 mutation is most frequently observed in del(5q) cases. Regarding -7/del(7q), 3 CDRs were located in 7q22, 7q34, and 7q35-36. Somatic mutations of the corresponding genes to each CDR (CUX1: 7q22, LUC7L2: 7q34, EZH2: 7q35-36) were identified, indicating that the loss of function or haploinsufficiency might result in the downstream pathological consequences. These recent findings have remarkably offered insights into genetic and clinical consequences in MDS/AML cases with del(5q) and -7/del(7q).


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 7/genética , Leucemia Mieloide Aguda/genética , RNA Helicases DEAD-box/genética , DNA Helicases/genética , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética
5.
Cytogenet Genome Res ; 158(3): 115-120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266029

RESUMO

Unbalanced translocations of Y-chromosomal fragments harboring the sex-determining region Y gene (SRY) to the X chromosome or an autosome result in 46,XX and 45,X testicular disorders of sex development (DSD), respectively. Of these, Y;autosome translocation is an extremely rare condition. Here, we identified a 20-year-old man with a 45,X,t(Y;7)(q11.21;q35) karyotype, who exhibited unilateral cryptorchidism, small testis, intellectual disability, and various congenital anomalies. The fusion junction of the translocation was blunt, and the breakpoint-flanking regions shared only 50% similarity. These results indicate that Y;autosome translocations can occur between 2 low-similarity sequences, probably via nonhomologous end joining. Furthermore, translocations of a Ypterq11.21 fragment to 7q35 likely result in normal or only mildly impaired male-type sexual development, along with various clinical features of 7q deletion syndrome, although their effects on adult testicular function remain to be studied.


Assuntos
Cromossomos Humanos Par 7/genética , Cromossomos Humanos Y/genética , Transtornos do Desenvolvimento Sexual/genética , Genes sry/genética , Doenças Testiculares/genética , Translocação Genética/genética , Adulto , Pontos de Quebra do Cromossomo , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Cariótipo , Masculino , Adulto Jovem
6.
BMC Med Genet ; 20(1): 118, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266487

RESUMO

BACKGROUND: Recessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Some patients also have a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome. A haplotype of variants upstream of SLC26A4, called CEVA, acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors. METHODS: This was a prospective cohort study of 114 individuals and 202 ears with EVA. To test our first hypothesis, we compared the thyroid and auditory phenotypes of subjects with mutations affecting coding regions of both alleles of SLC26A4 with those of subjects carrying CEVA in trans to mutations affecting the coding regions. To test our second hypothesis, we compared the phenotypes associated with the presence versus absence of CEVA among subjects with no coding region mutations, as well as among subjects with mutations affecting coding regions of both alleles. RESULTS: Subjects carrying CEVA in trans to a mutation of SLC26A4 have a normal thyroid phenotype and less severe hearing loss in comparison to individuals with mutations affecting coding regions of both alleles of SLC26A4. In subjects with no mutant alleles of SLC26A4, hearing loss was more severe in subjects who carry the CEVA haplotype in comparison to non-carriers. There was no correlation of CEVA with the phenotype of subjects with mutations affecting coding regions of both alleles. CONCLUSIONS: CEVA, acting as a likely pathogenic recessive allele, is associated with a less severe phenotype than alleles with a mutation affecting the coding regions or splice sites of SLC26A4. CEVA may act as a genetic modifier in patients with EVA caused by other factors.


Assuntos
Bócio Nodular/genética , Haplótipos , Perda Auditiva Neurossensorial/genética , Mutação , Fenótipo , Transportadores de Sulfato/genética , Aqueduto Vestibular/anormalidades , Aqueduto Vestibular/patologia , Adolescente , Adulto , Alelos , Audiometria , Criança , Pré-Escolar , Cromossomos Humanos Par 7/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Audição/genética , Perda Auditiva/genética , Heterozigoto , Homozigoto , Humanos , Masculino , Estudos Prospectivos , Sítios de Splice de RNA , Glândula Tireoide , Adulto Jovem
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 708-711, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302917

RESUMO

OBJECTIVE: To correlate genotype with clinical phenotype of a child featuring multiple congenital malformations. METHODS: Clinical examination of the patient was carried out. Chromosome microarray analysis (CMA) was employed to detect genomic copy number variations (CNVs), and quantitative PCR (qPCR) was used for verifying the result. RESULTS: The child had congenital heart disease (ventricular septal defect, atrial septal defect, pulmonary arterial hypertension, and tricuspid regurgitation), psychomotor retardation, agenesis of corpus callosum, hypospadias and scoliosis. CMA has detected a 1.8 Mb deletion at 7p22.3, a 1.8 Mb duplication at 7p22.3p22.2 and a 23.5 Mb duplication at 7q33q36.3 in the fetus, all of which were de novo in origin. CONCLUSION: CMA can precisely detect microdeletion/duplications and facilitate the genotype-phenotype correlation analysis.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Cardiopatias Congênitas/genética , Criança , Testes Genéticos , Humanos , Masculino , Fenótipo , Deleção de Sequência
8.
Cytogenet Genome Res ; 158(2): 88-97, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220833

RESUMO

Human chromosome 7 has been the focus of many behavioral, genetic, and medical studies because it carries genes related to cancer and neurodevelopment. We examined the evolution of the chromosome 7 homologs, and the 7q31 region in particular, using chromosome painting analyses and 3 paint probes derived from (i) the whole of chimpanzee chromosome VII (wcVII), (ii) human 7q31 (h7q31), and (iii) the chimpanzee homolog VIIq31 (cVIIq31). The wcVII probe was used instead of the whole human chromosome 7 because the chimpanzee contains additional C-bands and revealed large areas of synteny conservation as well as fragmentation across 20 primate species. Analyses focusing specifically on the 7q31 homolog and vicinity revealed considerable conservation across lineages with 2 exceptions. First, the probes verified an insertion of repetitive sequence at VIIq22 in chimpanzees and bonobos and also detected the sequence in most subtelomeres of the African apes. Second, a paracentric inversion with a breakpoint in the cVIIq31 block was found in the common marmoset, confirming earlier studies. Subsequent in silico comparative genome analysis of 17 primate species revealed that VIIq31.1 is more significantly conserved at the sequence level than other regions of chromosome VII, which indicates that its components are likely responsible for critical shared traits across the order, including conditions necessary for proper human development and wellbeing.


Assuntos
Coloração Cromossômica/métodos , Cromossomos Humanos Par 7/genética , Cromossomos de Mamíferos/genética , Animais , Simulação por Computador , Sequência Conservada , Evolução Molecular , Humanos , Hibridização in Situ Fluorescente , Pan paniscus/genética , Pan troglodytes/genética , Primatas/genética , Homologia de Sequência do Ácido Nucleico
9.
Eur J Med Genet ; 62(7): 103671, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31100449

RESUMO

The growth factor binding protein 10 (GRB10) has been suggested as a candidate gene for Silver-Russell syndrome because of its localization in 7p12, its imprinting status, data from mice models and its putative role in growth. Based on a new patient with normal growth carrying a GRB10 deletion affecting the paternal allele and data from the literature, we conclude that the heterogeneous clinical findings in patients with copy number variations (CNVs) of GRB10 gene depend on the size and the gene content of the CNV. However, evidence from mouse and human cases indicate a growth suppressing role of GRB10 in prenatal development. As a result, an increase of active maternal GRB10 copies, e.g. by maternal uniparental disomy of chromosome 7 or duplications of the region results in intrauterine growth retardation. In contrast, a defective GRB10 copy might result in prenatal overgrowth, whereas the paternal GRB10 allele is not required for proper prenatal growth.


Assuntos
Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Proteína Adaptadora GRB10/genética , Fenótipo , Síndrome de Silver-Russell/genética , Adolescente , Desenvolvimento Fetal/genética , Humanos , Masculino , Síndrome de Silver-Russell/patologia
11.
BMC Med Genet ; 20(1): 27, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704416

RESUMO

BACKGROUND: Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes. METHODS: Sixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT. RESULTS: Strongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus. CONCLUSIONS: We identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks.


Assuntos
Cromossomos Humanos/genética , Técnicas de Genotipagem/métodos , Judeus/genética , Miopia/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/genética , Exoma , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Escore Lod , Masculino , Miopia/etnologia , Linhagem , RNA Longo não Codificante/genética
12.
Clin Lab ; 65(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775878

RESUMO

Myelodysplastic syndromes (MDS) with basophilia or eosinophilia are very rare and portend poor prognoses. We present a rare patient who had MDS with excess blasts as well as peripheral basophilia and concurrent bone marrow (BM) basophilia/eosinophilia. She had a complex karyotype including 5q and 7q deletions; however, no oncogenic mutations were observed on next-generation sequencing of 54 genes known to be frequently mutated in acute myeloid leukemia/MDS. Peripheral basophilia resolved after decitabine treatment. Ours is the first report to describe a genome-wide analysis and the use of decitabine to successfully treat basophilia in an MDS patient with concurrent BM basophilia/eosinophilia.


Assuntos
Deleção Cromossômica , Eosinofilia/genética , Estudo de Associação Genômica Ampla/métodos , Síndromes Mielodisplásicas/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Basófilos/efeitos dos fármacos , Basófilos/patologia , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 7/genética , Decitabina/uso terapêutico , Eosinofilia/sangue , Eosinofilia/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico
13.
PLoS One ; 14(2): e0211799, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30707743

RESUMO

Genomic imprinting is important for normal brain development and aberrant imprinting has been associated with impaired cognition. We studied the imprinting status in selected imprints (H19, IGF2, SNRPN, PEG3, MEST1, NESPAS, KvDMR, IG-DMR and ZAC1) by pyrosequencing in blood samples from longitudinal cohorts born in 1936 (n = 485) and 1921 (n = 223), and anterior hippocampus, posterior hippocampus, periventricular white matter, and thalamus from brains donated to the Aberdeen Brain Bank (n = 4). MEST1 imprint methylation was related to childhood cognitive ability score (-0.416 95% CI -0.792,-0.041; p = 0.030), with the strongest effect evident in males (-0.929 95% CI -1.531,-0.326; p = 0.003). SNRPN imprint methylation was also related to childhood cognitive ability (+0.335 95%CI 0.008,0.663; p = 0.045). A significant association was also observed for SNRPN methylation and adult crystallised cognitive ability (+0.262 95%CI 0.007,0.517; p = 0.044). Further testing of significant findings in a second cohort from the same region, but born in 1921, resulted in similar effect sizes and greater significance when the cohorts were combined (MEST1; -0.371 95% CI -0.677,-0.065; p = 0.017; SNRPN; +0.361 95% CI 0.079,0.643; p = 0.012). For SNRPN and MEST1 and four other imprints the methylation levels in blood and in the five brain regions were similar. Methylation of the paternally expressed, maternally methylated genes SNRPN and MEST1 in adult blood was associated with cognitive ability in childhood. This is consistent with the known importance of the SNRPN containing 15q11-q13 and the MEST1 containing 7q31-34 regions in cognitive function. These findings, and their sex specific nature in MEST1, point to new mechanisms through which complex phenotypes such as cognitive ability may be inherited. These mechanisms are potentially relevant to both the heritable and non-heritable components of cognitive ability. The process of epigenetic imprinting-within SNRPN and MEST1 in particular-and the factors that influence it, are worthy of further study in relation to the determinants of cognitive ability.


Assuntos
Encéfalo/metabolismo , Cognição/fisiologia , Impressão Genômica/fisiologia , Proteínas/metabolismo , Proteínas Centrais de snRNP/sangue , Adulto , Idoso , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/metabolismo , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 7/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas/genética , Proteínas Centrais de snRNP/genética
14.
PLoS One ; 14(1): e0207353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30605476

RESUMO

BACKGROUND: Human endogenous retroviruses (HERV) comprise 8% of the human genome and can be classified into at least 31 families. Increased levels of transcripts from the W and H families of HERV have been observed in association with human diseases, such as multiple sclerosis and schizophrenia. Although HERV transcripts have been detected in many tissues and cell-types based on microarray and PCR studies, the extent of HERV expression in different cell-types and diseases state has been less comprehensively studied. RESULTS: We examined overall transcription of HERV, and particularly of HERV-W and HERV-H elements in human postmortem brain samples obtained from individuals with psychiatric diagnoses (n = 111) and healthy controls (n = 51) by analyzing publicly available RNA sequencing datasets. Sequence reads were aligned to prototypical sequences representing HERV, downloaded from Repbase. We reported a consistent expression (0.1~0.2% of mappable reads) of different HERV families across three regions of human brains. Spearman correlations revealed highly correlated expression levels between three brain regionsacross 475 consensus sequences. By mapping sequences that aligned to the consensus sequences of HERV-W and HERV-H families to individual loci on chromosome 7, more than 60 loci from each family were identified, part of which are being transcribed. The ERVWE1, locus located at chr7q21.2, exhibited high levels of transcription across the three datasets. Notably, we demonstrated a trend of increased expression of overall HERV, as well as HERV-W family in samples from both schizophrenia and bipolar disorder patients. CONCLUSIONS: The current analyses indicate that RNA sequencing is a useful approach for investigating global expression of repetitive elements, such as HERV, in the human genome. HERV-W/H with the tendency of transcription up-regulation in patients suggests potential implication of HERV-W/H in psychiatric diseases.


Assuntos
Encéfalo/metabolismo , Encéfalo/virologia , Retrovirus Endógenos/genética , Análise de Sequência de RNA , Transcrição Genética , Transtorno Bipolar/genética , Transtorno Bipolar/virologia , Cromossomos Humanos Par 7/genética , Depressão/genética , Depressão/virologia , Regulação Viral da Expressão Gênica , Loci Gênicos , Genoma Humano , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sequências Repetitivas de Ácido Nucleico/genética , Esquizofrenia/genética , Esquizofrenia/virologia , Estatísticas não Paramétricas
15.
Medicine (Baltimore) ; 97(45): e13094, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30407316

RESUMO

RATIONALE: Chromosome deletion/duplication has been reported to be associated with mental disability and dysmorphism according to the accumulated research evidence. PATIENT CONCERNS: A 25-year-old woman underwent amniocentesis for cytogenetic and single-nucleotide polymorphism (SNP) array analysis at 18 weeks of gestation due to the increased Down syndrome risk of 1/13. DIAGNOSES: The fetal chromosomal analysis revealed a seemingly "normal" chromosomal karyotype, but the SNP array results showed a partial duplication of chromosome 4q34.1q35.2 and a deletion of chromosome 7q34q36.3fluorescence in situ hybridization (FISH) analysis showed that the couple had normal chromosome 4 and 7, whereas there was a partial signal fragment of chromosome 4 attached on the long arm of chromosome 7 for the fetus. INTERVENTIONS: The couple finally chose to terminate the pregnancy based on the ultrasonic multiple malformations and the abnormal SNP array results. OUTCOMES: The duplicated/deleted segments of the fetus were de novo. Meanwhile, we consider SHH and XRCC2 as good candidate genes, which may, in part, explain the observed abnormalities for the fetus. LESSONS: The combination of SNP array and FISH analysis can give a molecular chromosomal diagnosis, which will offer more clear cytogenetic diagnosis and genetic counseling.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Feto/diagnóstico por imagem , Trissomia/diagnóstico , Aborto Induzido , Adulto , Cromossomos Humanos Par 4 , Feminino , Humanos , Gravidez , Ultrassonografia Pré-Natal
16.
Anticancer Res ; 38(7): 3961-3966, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29970518

RESUMO

Since the introduction of tyrosine kinase inhibitors (TKI), the prospects for patients with chronic myeloid leukemia (CML) have improved significantly. Herein we present the case of a patient with CML who experienced blast crisis and development of acute myeloid leukemia (AML) 10 years after presentation. The CML was characterized by the gene fusion of breakpoint cluster region BCR and tyrosine-protein kinase ABL1. During treatment different therapeutic protocols including imatinib, nilotinib, dasatinib and ponatinib were applied due to development of resistance or non-response. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used to describe cytogenetic and molecular aberrations elucidating the development into AML: A loss of chromosome 7, as well as an arising frequency of variants in the gene met proto-oncogene MET (p.T110I) and tyrosine-protein phosphatase non-receptor type 11 PTPN11 (p.Q510L) was observed. This report describes the comprehensive characterization of a clinical case showing multiple therapeutic resistances correlated with genetic aberrations.


Assuntos
Crise Blástica/genética , Crise Blástica/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Mutação , Antineoplásicos/uso terapêutico , Crise Blástica/tratamento farmacológico , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Resistencia a Medicamentos Antineoplásicos , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
17.
Eur J Gastroenterol Hepatol ; 30(8): 828-837, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29787419

RESUMO

BACKGROUND: Approximately 5% of patients with celiac disease (CeD) do not respond to a gluten-free diet and progress to refractory celiac disease (RCD), a severe progression that is characterized by infiltration of intraepithelial T lymphocytes. Patients with RCD type II (RCDII) show clonal expansions of intraepithelial T lymphocytes that result in a poor prognosis and a high mortality rate through development of aggressive enteropathy-associated T-cell lymphoma. It is not known whether genetic variations play a role in severe progression of CeD to RCDII. PATIENTS AND METHODS: We performed the first genome-wide association study to identify the causal genes for RCDII and the molecular pathways perturbed in RCDII. The genome-wide association study was performed in 38 Dutch patients with RCDII, and the 15 independent top-associated single nucleotide polymorphism (SNP) variants (P<5×10) were replicated in 56 independent French and Dutch patients with RCDII. RESULTS: After replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10, odds ratio=2.36) but not with CeD susceptibility. SNP rs2041570 risk allele A was associated with lower levels of FAM188B expression in blood and small intestinal biopsies. Stratification of RCDII biopsies based on rs2041570 genotype showed differential expression of innate immune and antibacterial genes that are expressed in Paneth cells. CONCLUSION: We have identified a novel SNP associated with the severe progression of CeD to RCDII. Our data suggest that genetic susceptibility to CeD might be distinct from the progression to RCDII and suggest a role for Paneth cells in RCDII progression.


Assuntos
Doença Celíaca/genética , Cromossomos Humanos Par 7/genética , Polimorfismo de Nucleotídeo Único , Biópsia , Estudos de Casos e Controles , Doença Celíaca/diagnóstico , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Dieta Livre de Glúten , Progressão da Doença , Feminino , França , Microbioma Gastrointestinal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Imunidade Inata/genética , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Masculino , Proteínas de Membrana/genética , Análise Multivariada , Países Baixos , Razão de Chances , Celulas de Paneth/imunologia , Celulas de Paneth/microbiologia , Celulas de Paneth/patologia , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença , Falha de Tratamento
18.
Ital J Pediatr ; 44(1): 59, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29801510

RESUMO

BACKGROUND: Currarino syndrome is a rare condition characterized by presacral mass, anorectal malformation and sacral dysgenesis. CASE PRESENTATION: We report the case of a child that presented chronic constipation, encopresis and mycrocephaly. The characteristics were initially compatible with a case of functional constipation and a therapy with polyethylene glycol was prescribed. After a year, because of poor response, a plain abdominal X-ray was performed, detecting sacrum abnormalities. Finally, a CGH-array analysis was performed and a form of Currarino Syndrome caused by a rare 7q36 microdeletion, was diagnosed. CONCLUSION: Occult spinal dysraphism should be suspected in case of poor polyethylene glycol responder constipation, even when evident sacral abnormalities on the physical examination are not detected.


Assuntos
Canal Anal/anormalidades , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Anormalidades do Sistema Digestório/diagnóstico , Anormalidades do Sistema Digestório/genética , Microcefalia/diagnóstico , Microcefalia/genética , Reto/anormalidades , Sacro/anormalidades , Siringomielia/diagnóstico , Siringomielia/genética , Pré-Escolar , Feminino , Proteínas de Homeodomínio/genética , Humanos , Fatores de Transcrição/genética
19.
Clin Chim Acta ; 481: 171-176, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29550276

RESUMO

BACKGROUND: Williams-Beuren syndrome (WBS) is caused by a microdeletion of chromosome arm 7q11.23. A rapid and inexpensive genotyping method to detect microdeletion on 7q11.23 needs to be developed for the diagnosis of WBS. This study describes the development of a new type of molecular diagnosis method to detect microdeletion on 7q11.23 based upon high-resolution melting (HRM). METHODS: Four genes on 7q11.23 were selected as the target genes for the deletion genotyping. dNTP-limited duplex PCR was used to amplify the reference gene, CFTR, and one of the four genes respectively on 7q11.23. An HRM assay was performed on the PCR products, and the height ratio of the negative derivative peaks between the target gene and reference gene was employed to analyze the copy number variation of the target region. RESULTS: A new genotyping method for detecting 7q11.23 deletion was developed based upon dNTP-limited PCR and HRM, which cost only 96 min. Samples from 15 WBS patients and 12 healthy individuals were genotyped by this method in a blinded fashion, and the sensitivity and specificity was 100% (95% CI, 0.80-1, and 95% CI, 0.75-1, respectively) which was proved by CytoScan HD array. SIGNIFICANCE: The HRM assay we developed is an rapid, inexpensive, and highly accurate method for genotyping 7q11.23 deletion. It is potentially useful in the clinical diagnosis of WBS.


Assuntos
Cromossomos Humanos Par 7/genética , Desoxirribonucleotídeos/genética , Síndrome de Williams/genética , Pré-Escolar , Deleção Cromossômica , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase
20.
Blood Cancer J ; 8(3): 28, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29515104

RESUMO

Clonal cytogenetic evolution (CE) (i.e., acquisition of new chromosomal aberrations over time) is relevant for the progression of myelodysplastic syndromes (MDS). We performed detailed analysis of CE in 729 patients with MDS and related disorders. Patients with CE showed shorter survival (median OS 18.0 versus 53.9 months; P < 0.01), higher leukemic transformation rate (48.0% versus 21.4%; P < 0.01) and shorter intervals to leukemic transformation (P < 0.01). Two main CE patterns were detected: early versus late CE (median onset 5.3 versus 21.9 months; P < 0.01) with worse survival outcomes for early CE. In the case of CE, del (7q)/-7 (P = 0.020) and del (17p) (P = 0.002) were especially unfavorable. Extending the evolution patterns from Tricot et al. (1985) forming five subgroups, prognosis was best (median OS not reached) in patients with "transient clones/changing clone size", whereas those with "CE at diagnosis" showed very poor outcomes (P < 0.01 for comparison of all). Detailed sequential cytogenetic analysis during follow-up improves prognostication in MDS patients and acknowledges the dynamic biology of the disease. Evidence, time-point, and patterns of cytogenetic clonal evolution should be included into future prognostic scoring systems for MDS.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 7/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Taxa de Sobrevida
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