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1.
BMC Med Genet ; 21(1): 202, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046021

RESUMO

BACKGROUND: Metanephric adenoma (MA) is a rare benign renal neoplasm. On occasion, MA can be difficult to differentiate from renal malignancies such as papillary renal cell carcinoma in adults and Wilms̕ tumor in children. Despite recent advancements in tumor genomics, there is limited data available regarding the genetic alterations characteristic of MA. The purpose of this study is to determine the frequency of metanephric adenoma cases exhibiting cytogenetic aberration t (9;15)(p24;q24), and to investigate the association between t (9,15) and BRAF mutation in metanephric adenoma. METHODS: This study was conducted on 28 archival formalin fixed paraffin-embedded (FFPE) specimens from patients with pathologically confirmed MA. Tissue blocks were selected for BRAF sequencing and fluorescent in situ hybridization (FISH) analysis for chromosomal rearrangement between KANK1 on chromosome 9 (9p24.3) and NTRK3 on chromosome 15 (15q25.3), which was previously characterized and described in two MA cases. RESULTS: BRAFV600E mutation was identified in 62% of our cases, 9 (38%) cases were BRAFWT, and 4 cases were uninformative. Of the 20 tumors with FISH results, two (10%) were positive for KANK1-NTRK3 fusion. Both cases were BRAFWT suggesting mutual exclusivity of BRAFV600E and KANK1-NTRK3 fusion, the first such observation in the literature. CONCLUSIONS: Our data shows that BRAF mutation in MA may not be as frequent as suggested in the literature and KANK-NTRK3 fusions may account for a subset of BRAFWT cases in younger patients. FISH analysis for KANK1-NTRK3 fusion or conventional cytogenetic analysis may be warranted to establish the diagnosis of MA in morphologically and immunohistochemically ambiguous MA cases lacking BRAF mutations.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adenoma/genética , Proteínas do Citoesqueleto/genética , Neoplasias Renais/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas B-raf/genética , Receptor trkC/genética , Adenoma/patologia , Adolescente , Adulto , Idoso , Criança , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Translocação Genética , Adulto Jovem
2.
Hematol Oncol ; 38(4): 607-610, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32602167
3.
N Engl J Med ; 383(16): 1522-1534, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32558485

RESUMO

BACKGROUND: There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19. METHODS: We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels. RESULTS: We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10-8) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10-10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10-8, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10-4) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10-5). CONCLUSIONS: We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.).


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Betacoronavirus , Cromossomos Humanos Par 3/genética , Infecções por Coronavirus/genética , Predisposição Genética para Doença , Pneumonia Viral/genética , Polimorfismo de Nucleotídeo Único , Insuficiência Respiratória/genética , Idoso , Estudos de Casos e Controles , Cromossomos Humanos Par 9/genética , Infecções por Coronavirus/complicações , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Família Multigênica , Pandemias , Pneumonia Viral/complicações , Insuficiência Respiratória/etiologia , Espanha
4.
Nat Med ; 26(6): 909-918, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32472114

RESUMO

PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Apresentação do Antígeno/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Deleção Cromossômica , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Feminino , Imunofluorescência , Deleção de Genes , Genômica , Antígenos de Histocompatibilidade Classe II/genética , Histona Desmetilases/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Prognóstico , Complexo de Endopeptidases do Proteassoma/genética , Análise de Sequência de RNA , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Sequenciamento Completo do Exoma
5.
Cancer Genet ; 243: 48-51, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32272434

RESUMO

Traditional cytogenetic testing methodologies, including conventional chromosome analysis and fluorescence in situ hybridization (FISH), are invaluable for the detection or recurrent genetic abnormalities in various hematologic malignancies. However, technological advances, including a novel next-generation sequencing technique termed mate-pair sequencing (MPseq), continue to revolutionize the field of cytogenetics by enabling the characterization of structural variants at a significantly higher resolution compared to traditional methodologies. To illustrate the power of MPseq, we present a 27-year-old male diagnosed with chronic myeloid leukemia in myeloid blast crisis with multiple chromosomal abnormalities observed in all 20 metaphases from a peripheral blood specimen, including t(9;22)(q34;q11.2) and t(4;11)(q12;p15). Suspicious of a novel NUP98/PDGFRA fusion [t(4;11)(q12;p15)], break-apart FISH probe sets for the PDGFRA (4q12) and NUP98 (11p15.4) gene regions were performed and were both positive in approximately 86% of 200 interphase nuclei. However, subsequent MPseq testing revealed breakpoints located within the NUP98 gene and within an intergenic region (4q12) located between the CHIC2 and PDGFRA genes, indicating this 4;11 translocation does not result in the predicted NUP98/PDGFRA gene fusion as inferred from FISH and conventional chromosome results. This case demonstrates the clinical utility of MPseq, particularly for characterizing novel gene fusion events which may ultimately identify a false-positive FISH result.


Assuntos
Crise Blástica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas de Fusão Oncogênica/isolamento & purificação , Adulto , Crise Blástica/diagnóstico , Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 9/genética , Análise Citogenética , Progressão da Doença , Reações Falso-Positivas , Humanos , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
6.
Am J Hematol ; 95(6): 691-709, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32239758

RESUMO

DISEASE OVERVIEW: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL oncoprotein. FRONTLINE THERAPY: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first-line treatment of newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses, but they had no impact on survival prolongation, likely because of the existence of highly effective salvage therapies for patients who have a cytogenetic relapse with frontline TKI. SALVAGE THERAPY: For CML post failure on frontline therapy, second-line options include second and third generation TKIs. Although potent and selective, these exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least 2 TKIs, and for all patients in advanced phase disease. Even among older patients who have a cytogenetic relapse post failure on all TKIs, they can maintain long-term survival if they continue on a daily most effective/less toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan, others).


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases/uso terapêutico , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 9/genética , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Monitorização Fisiológica , Inibidores de Proteínas Quinases/efeitos adversos , Taxa de Sobrevida , Translocação Genética
7.
BMJ Case Rep ; 13(3)2020 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-32152069

RESUMO

​The advance in the human genetic field has permitted to identify small chromosome alterations and associate them to a specific phenotype. However, there are many mutations that have not yet been described in the literature. We describe the clinical case of a term newborn with appropriate weight to its gestational age, without perinatal background of interest that, at birth, presented: macrocephaly, hypertelorism, low-set ears, prominent forehead, micrognathia, camptodactyly, bilateral cryptorchidism, inspiratory stridor with the cry, multifocal systolic murmur, wide anterior fontanel and hypotonia of mixed characteristics and in whom a deletion of the 1q44 cytoband and a pathogenic duplication in the 9q32q34.3 cytoband were detected. We perform a review of the literature.


Assuntos
Anormalidades Múltiplas/genética , Duplicação Cromossômica , Fenótipo , Deleção de Sequência , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 9 , Técnicas de Genotipagem , Humanos , Recém-Nascido , Masculino
8.
J Cardiovasc Pharmacol ; 75(5): 439-445, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32079855

RESUMO

OBJECTIVE: To study the interaction effects of rs10757278 polymorphisms at 9p21 locus and traditional risk factors on coronary heart disease (CHD) in Xinjiang, China. METHODS: This case-control study consecutively enrolled 310 unrelated consecutive CHD patients aged 18-70 years old. All study participants were recruited between January and December 2017 from The Heart Center of The First Affiliated Hospital of Xinjiang Medical University. CHD patients were confirmed by coronary angiography (≥50% diameter stenosis in at least one of the major coronary arteries) according to the American Heart Association criteria for the confirmation of CHD. Healthy subjects were randomly selected from the occupational population, who received physical examination in our hospital and matched to cases on the basis of age (±3 years) and sex, those without medical history of cardiovascular diseases, and 536 subjects were selected as the control group after medical history inquiry, physical examination, cardiac ultrasound, electrocardiogram, and other blood biochemical examinations in the hospital. The occupational stress was evaluated by an effort-reward imbalance questionnaire. An epidemiological survey was conducted to collect clinical data. Chi-squared test, analysis of variance, and binary logistic regression analysis were adopted. RESULTS: Both the case and the control groups showed significant difference in smoking, drinking, physical activity, hypertension, diabetes mellitus, family history of CHD, and body mass index (BMI) (all P < 0.05); prevalence of CHD was not related to occupational stress. There was no significant difference in occupational stress level between the 2 groups (P > 0.05); Differences in rs10757278 genotype between the case group and the control groups were statistically significant; binary logistic regression analysis was used to evaluate the risk factors of CHD. After adjustment for age and sex, significant increased risk effects for CHD were found to be associated with smoking [odds ratio (OR) = 2.311; 95% confidence interval (CI): 1.04-2.499; P < 0.001], physical exercise (OR = 1.365; 95% CI: 1.137-1.639; P < 0.001), hypertension (OR = 4.627; 95% CI: 2.165-10.764; P < 0.001), family history of CHD (OR = 4.103; 95% CI: 3.169-6.892; P < 0.001), BMI (OR = 2.484; 95% CI: 2.036-3.03; P < 0.001), and GG genotype at rs10757278 (OR = 1.978; 95% CI: 1.413-2.769; P < 0.001); We noted that a significant interaction association between GG genotype at rs10757278 and CHD differs across categories of smoking, hypertension, family history of CHD, and BMI. CONCLUSION: GG genotype at rs10757278 may be a risk factor for CHD. And there are interaction effects between GG genotype of rs10757278 in region 9p21 gene and traditional risk factors.


Assuntos
Cromossomos Humanos Par 9 , Doença das Coronárias/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Medição de Risco , Fatores de Risco , Adulto Jovem
9.
Int J Mol Sci ; 21(4)2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32098246

RESUMO

Circulating tumor cells (CTCs) are promising biomarkers for prognosis, therapeutic response prediction, and treatment monitoring in cancer patients. Despite its epithelial origin, renal cell carcinoma (RCC) shows low expression of epithelial markers hindering CTC-enrichment approaches exploiting epithelial cell surface proteins. In 21 blood samples serially collected from 10 patients with metastatic RCC entering the TARIBO trial, we overcame this limitation using the marker-independent Parsortix™ approach for CTC-enrichment coupled with positive and negative selection with the DEPArray™ with single cell recovery and analysis for copy number alterations (CNA) by next generation sequencing NGS. Two CTC subpopulations were identified: epithelial CTC (eCTC) and non-conventional CTC (ncCTC) lacking epithelial and leukocyte markers. With a threshold ≥1CTC/10 mL of blood, the positivity rates were 28% for eCTC, 62% for ncCTCs, and 71% considering both CTC types. In two patients with detectable eCTCs at baseline, progression free survival was less than 5 months. In an index case, hierarchical structure by translational oncology (TRONCO) identified three clones among 14 CTCs collected at progression and at baseline, each containing cells with a 9p21.3loss, a well-known metastasis driving subclonal alteration. CTCs detection in RCC can be increased by marker-independent approaches, and CTC molecular characterization can allow detection of subclonal events possibly related to tumor progression.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Neoplasias Renais , Células Neoplásicas Circulantes , Análise de Célula Única , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia
10.
Hematol Oncol ; 38(2): 171-180, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31955451

RESUMO

We described four patients with diffuse large B-cell lymphoma (DLBCL) carrying t(9;14)(p13;q32) that places the PAX5 adjacent to the immunoglobulin heavy chain (IGH) gene. Ages ranged between 63 and 80, and three were female. One developed a nodal disease, and the other three involved extranodal organs. The lymphoma cells were CD10- /BCL6- /MUM1+ in three and CD10+ /BCL6+ /MUM1+ in one. BCL2 was weak or negative. All had t(9;14)(p13;q32), and three had additional 14q32/IGH translocations or +der(14)t(9;14)(p13;q32). Fluorescence in situ hybridization using the PAX5 break-apart probe showed that the locus was disrupted between the 5' and 3' probes or within the 5' probe. Immunohistochemistry (IHC) using a monoclonal antibody against PAX5 showed strong nuclear positivity in all four patients. Cell block IHC of a CD30+ DLBCL cell line, KIS-1, which carried the t(9;14)(p13;q32) and PAX5-IGH fusion gene, reproduced the CD10- /BCL6- /MUM1+ immunophenotype, low-level BCL2, and strong nuclear PAX5. Uniform nuclear positivity of MUM1 in all four cases and KIS-1 cells suggest that these lymphomas arose at a late stage of B-cell differentiation, where expression of PAX5 physiologically becomes downregulated. It is therefore possible that high-level PAX5 resulting from t(9;14)(p13;q32) at this stage of differentiation perturbs the plasma cell differentiation program initiated by PAX5 repression, thereby contributing to the development of a fraction of DLBCL.


Assuntos
Núcleo Celular/metabolismo , Cadeias Pesadas de Imunoglobulinas/genética , Imuno-Histoquímica/métodos , Fatores Reguladores de Interferon/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Fator de Transcrição PAX5/metabolismo , Translocação Genética , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Fatores Reguladores de Interferon/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX5/genética , Prognóstico
11.
Eur J Nutr ; 59(1): 35-43, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30600348

RESUMO

PURPOSE: Gene-dietary patterns may contribute to determining body composition and related biochemical indices. The aim of this study was to evaluate interactions between rs1333048 polymorphism and major dietary patterns on body fat percentage, general and central obesity, and related biochemical measurements. METHODS: This cross-sectional study was conducted on 265 healthy Tehrani adults with mean age of 35 years (47.5% men, 52.5% women). Dietary patterns (DPs) were extracted by factor analysis. Bioelectrical impedance analysis was used for body analysis and rs1333048 was genotyped by the restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Three DPs were extracted: restricted refined grains DP, legumes DP and healthy DP. AA genotype compared to CC genotype had greater odds for general obesity before (OR 3.14; 95% CI 1.008-9.60, P = 0.045) and after (OR 3.11; 95% CI 1.008-9.60, P = 0.048) adjusting for potential confounders. Individuals with AA genotype were more likely to be centrally obese before (OR 2.09; 95% CI 1.006-4.35, P = 0.048) and after (OR 2.63; 95% CI 1.12-6.17, P = 0.026) controlling for potential confounders. Significant interactions were observed between Legumes DP and rs1333048 SNP on waist circumference (P = 0.047), body fat % (BFP) (P = 0.048), hs-Crp (P = 0.042), BMI (P = 0.073), WHtR (P = 0.063) and odds for general obesity (P = 0.051). Following this DP reduced all these items for individuals with CC genotype, whereas increased them for people who carry CA or AA genotypes. CONCLUSIONS: The findings indicate that there are significant associations between AA genotype of rs1333048 SNP and general and central obesity, and significant interaction between alleles of this SNP and major dietary patterns on the odds of general obesity, BFP, waist circumference, BMI, WHtR and hs-Crp.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Cromossomos Humanos Par 9/genética , Dieta/métodos , Obesidade/epidemiologia , Obesidade/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Estudos Transversais , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
12.
Eur J Med Genet ; 63(1): 103618, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30684669

RESUMO

A small heterozygous deletion involving KANK1 was originally reported in 2005 to cause cerebral palsy in one large Israeli family of Jewish Moroccan origin. There were nine affected children over two generations to five unaffected fathers. All of these children had congenital hypotonia that evolved into spastic quadriplegia over the first year of life, along with intellectual impairment and brain atrophy. The subsequent clinical depictions of other individuals with neurological disease harbouring a comparable KANK1 deletion have been extremely variable and most often quite dissimilar to the original family. The reported pathogenicity of these deletions has also been variable, due to an inconsistent nature of reported disease associations and limited data. We therefore sought to perform a review of the significance of small distal interstitial chromosome 9p24.3 deletions principally involving KANK1, including data from the VCGS cytogenetics laboratory. We found that carrier parents do not appear to display an increased frequency of neurological disease, individuals with a small KANK1 deletion have sometimes been found to have an alternate genetic diagnosis that explained their neurological condition, and small KANK1 deletions can be seen with approximate equal frequency in case and control populations. These data led us to conclude that small deletions involving KANK1 do not cause a highly-penetrant influence of large effect size and they are unlikely to contribute significantly to the aetiology of disease in patients with development delay, intellectual disability, autism or cerebral palsy. We recommend searching for an alternate explanation for disease in individuals with a neurological disorder found to have a small deletion involving KANK1.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Paralisia Cerebral/genética , Proteínas do Citoesqueleto/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Paralisia Cerebral/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 9/genética , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/patologia , Feminino , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/patologia , Masculino , Linhagem , Deleção de Sequência/genética , Adulto Jovem
13.
Laryngoscope ; 130(8): 2028-2033, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31750954

RESUMO

Kleefstra syndrome is a rare neurogenetic disorder caused by a subtelomeric 9q34.3 deletion or by an intragenic mutation of the euchromatin histone methyl transferase 1 gene (EHMT1). Approximately 20% to 30% of individuals have hearing loss. The left temporal bone of one subject with hearing loss was studied using light microscopy. There were several abnormalities including dysostosis of the stapes without fixation, enlarged vestibular aqueduct, anomalies of the organ of Corti in the basal turn, cyst formation in the stria vascularis, and dysmorphia of the cochlear modiolus and the vestibular labyrinth. This is the first published description of the otopathology in Kleefstra syndrome. Laryngoscope, 130:2028-2033, 2020.


Assuntos
Anormalidades Craniofaciais/complicações , Perda Auditiva/etiologia , Cardiopatias Congênitas/complicações , Deficiência Intelectual/complicações , Adolescente , Deleção Cromossômica , Cromossomos Humanos Par 9 , Evolução Fatal , Humanos , Masculino
14.
Am J Dermatopathol ; 42(3): 204-207, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31449064

RESUMO

We report a case of a polypoid atypical Spitz tumor with a prominent fibrosclerotic stromal component, harboring a CLIP2-BRAF fusion, which has hitherto been not reported in melanocytic lesions. The neoplasm occurred in a 78-year-old male patient and appeared microscopically as a predominantly dermal, barely symmetrical, polypoid lesion composed mainly of epithelioid cells showing moderate degree of nuclear pleomorphism with ample amphophilic cytoplasm arranged in nests, fascicles, or single units. The mitotic rate was 2/mm, and the mitoses were confined to the upper portion of the lesion. The Breslow thickness was 2.3 mm. The stroma contained conspicuous plumped fibroblasts and thickened collagen bundles associated with dilated medium-sized vessels. Focally, sclerotic areas were found. A moderately dense, lymphocyte-predominant inflammatory infiltrate scattered through the whole lesion was seen. Despite strong nuclear and cytoplasmic positivity of p16, FISH revealed homozygous loss in locus 9p21. A CLIP2-BRAF fusion was found by next-generation sequencing. No other genetic alterations including a TERT-promoter mutation was found. The patient is disease-free without recurrence or evidence of metastatic disease after 5 years and 2 months of follow-up.


Assuntos
Nevo de Células Epitelioides e Fusiformes/genética , Nevo de Células Epitelioides e Fusiformes/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Idoso , Aberrações Cromossômicas , Cromossomos Humanos Par 9/genética , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/genética , Fusão Oncogênica , Proteínas Proto-Oncogênicas B-raf/genética
15.
Med Arch ; 73(5): 311-315, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31819303

RESUMO

Introduction: Acute lymphoblastic leukemia (ALL) is one of the most common cancers in children and accounts for about ⅓ of cancers in children. The annual incidence of ALL is 4 patients per 100,000 children. Their peak age is between 2-5 Year. One of the most important prognostic factors is cytogenetic abnormalities which are very effective in determining treatment policy. Aim: To determine the frequency of cytogenetic findings and its effect on the outcome of children with ALL. Materials and Methods: This retrospective cross-sectional analytical study was conducted on children with ALL who their disease was diagnosed between 2001and 2009. Furthermore, 206 patients with ALL were examined by referring to Clinic of Ali Asghar Hospital in Tehran. Data was collected from medical records and analyzed by SPSS16 software. Results: 206 children with ALL were enrolled in the study. The estimated event-free survival rate of all enrolled patients was more than 70%. There was a significant relationship between type of cytogenetic disorder and clinical outcome of patients (P˂0.0001), where the highest mortality was observed in patients with t (9;22) and t (4;11). There was no significant correlation between the sex and age with the clinical outcome of the patient (P = 0.064; p=0.322). There was a statistically significant relationship between mediastinal mass and clinical outcome (P = 0.002), indicating that the presence of cells growth in an involuntary way can be cause of the cancer. A significant association was found between the clinical outcome of patients and radiotherapy (P = 0.043), indicating that radiotherapy is effective in improving cancer. Conclusion: The findings demonstrated that the average survival rate without recurrence in children was at level of the European countries. However, the strong chemotherapy weakened the role of many prognostic factors in ALL patients, but some translocations are prognostic factors in predicting death in patients with ALL. Therefore, patients with this factor need to receive more confident treatment policy. Comprehensive studies are required by focusing on more samples because of low number of relapses and deaths in the present study.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 22 , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 9 , Estudos Transversais , Diploide , Síndrome de Down/genética , Feminino , Humanos , Lactente , Irã (Geográfico) , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Intervalo Livre de Progressão , Radioterapia , Estudos Retrospectivos
16.
Scand J Gastroenterol ; 54(12): 1441-1447, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31814461

RESUMO

Background: Intestinal degenerative neuropathy without extra-intestinal involvement occurs as familial forms (FIDN) but the genetics behind is unknown. We studied a Swedish family with autosomal dominant disease and several cases of chronic intestinal pseudo-obstruction (CIP).Methods: We included 33 members of a family sharing a male ancestor. Chronic intestinal symptoms including diarrhoea occurred in 11, four had severe CIP. DNA was analysed with SNP-microarray (Affymetrix), linkage (Allegro Software) and gene dosage (CNAG 3.0).Results: Genetic linkage was found to the short arm of Ch9 to a 9.7 Mb region with 45 protein-coding genes, 22 of which were duplicated (1.2 Mb duplication) (dup(9)(p21.3) with breaking point in the FOCAD-gene. Lod score for the region was 3.4. Fourteen subjects were duplication carriers including all 11 subjects having severe chronic symptoms/CIP. Nineteen subjects had no duplication. The occurrence of gastrointestinal symptoms in the family was strongly linked to duplication carrier-ship (p = .0005). The two branches of the family had separate maternal ancestors (A and B). Including the previous generation, severe disease (overt CIP and/or death from intestinal failure) was assessed to occur in 100% (5/5) of duplication carriers in branch A and in 21% (3/14) in branch B (p = .005). In branch B the onset of symptoms was later (median 38 vs. 24 yrs) and three duplication carriers were symptom-free.Conclusions: In this family with autosomal dominant hereditary intestinal neuropathy, the disorder is linked to a 9.7 Mb region in Ch9 including a 1.2 Mb duplication. There is a significant difference in disease expressivity between family branches, seemingly related to separate maternal ancestors.


Assuntos
Cromossomos Humanos Par 9 , Diarreia , Transtornos Heredodegenerativos do Sistema Nervoso , Pseudo-Obstrução Intestinal , Intestinos , Proteínas do Tecido Nervoso/genética , Adulto , Doença Crônica , Diarreia/diagnóstico , Diarreia/etiologia , Família , Feminino , Duplicação Gênica , Loci Gênicos , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Transtornos Heredodegenerativos do Sistema Nervoso/epidemiologia , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Pseudo-Obstrução Intestinal/epidemiologia , Pseudo-Obstrução Intestinal/etiologia , Pseudo-Obstrução Intestinal/fisiopatologia , Intestinos/inervação , Intestinos/fisiopatologia , Masculino , Linhagem , Índice de Gravidade de Doença , Suécia/epidemiologia
17.
Sci Rep ; 9(1): 18405, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804579

RESUMO

The interaction of genetic susceptibility and dietary habits in cardiovascular disease (CVD) remains undetermined. The purpose of this study was to investigate whether a Mediterranean dietary style modified the genetic risk of developing CVD in a Chinese cohort. A total of 2098 subjects with dietary information from a Chinese community cohort (CVDFACTS) were enrolled. Candidate genes, including SNP markers rs1333049 (CDKN2B, 9p21.3), rs17465637 (MIA3, 1q41) and rs501120 (CXCL12, 10q11.21), were genotyped to analyze the association with future CVD. The impact of dietary pattern was also analyzed according to adherence to the diet using the Mediterranean Diet Score (MDS). After an average follow-up of 7.8 years, only the C risk allele of rs1333049 at chromosome 9p21.3 was associated with a higher risk of MI with either an additive [HR = 1.78, 95% CI:1.23-2.5] or a recessive model [HR = 2.40, 95% CI: 1.42-4.04], and the CC genotype had a higher risk of developing MI (p = 0.009, log-rank test). There was no significant difference in the association of the lipid profile with future CV outcomes among the MDS tertiles. However, the high MI risk of the CC genotype in individuals consuming a less healthy diet (MDS1) (HR: 6.39, 95% CI: 1.74-23.43) significantly decreased to 2.38 (95% CI: 0.57-10.04) in individuals consuming a healthier diet (MDS3), indicating that a healthier dietary pattern (higher MDS) modified the risk of developing MI in carriers of variants in CDKN2B. In conclusion, genetic variants of CDKN2B at 9p21 were significantly associated with future MI risk in a Chinese cohort, and the genetic risk of MI could be modified by a healthier diet.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Quimiocina CXCL12/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Dieta Mediterrânea , Infarto do Miocárdio/genética , Adulto , Idoso , Alelos , Translocador Nuclear Receptor Aril Hidrocarboneto/sangue , Grupo com Ancestrais do Continente Asiático , Quimiocina CXCL12/sangue , Cromossomos Humanos Par 9/química , Estudos de Coortes , Inibidor de Quinase Dependente de Ciclina p15/sangue , Feminino , Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
18.
Nat Commun ; 10(1): 4928, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666522

RESUMO

Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS.


Assuntos
Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Animais , Córtex Cerebral/citologia , Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Cromossomos Humanos Par 9/metabolismo , Anormalidades Craniofaciais/metabolismo , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Cardiopatias Congênitas/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas , Deficiência Intelectual/metabolismo , Mutação com Perda de Função , Masculino , Camundongos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Cultura Primária de Células , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Regulação para Cima
19.
J Assist Reprod Genet ; 36(12): 2557-2561, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31734857

RESUMO

PURPOSE: To report the unbalanced chromosome rearrangement rate and overall aneuploidy rate in day 5/6 embryos from a series of patients who underwent in vitro fertilization (IVF) with preimplantation genetic testing for structural rearrangements (PGT-SR) for the pericentric inversion 9 variant, inv(9)(p11q13) or inv(9)(p12q13), with concurrent 24 chromosome preimplantation genetic testing for aneuploidy (PGT-A). METHODS: This was a retrospective cohort analysis. IVF cycles and embryo biopsies were performed by referring clinics. Fifty-two trophectoderm biopsy samples from seven couples were sent to a single lab for PGT-SR for an inversion 9 variant with concurrent 24 chromosome PGT-A using single-nucleotide polymorphism (SNP) microarrays with bioinformatics. RESULTS: The unbalanced rearrangement rate for this embryo cohort was 0/52 (0.0%); mean maternal age per embryo was 33.3 years (range 21-39 years). The overall euploid rate was 61.5% and aneuploidy rate was 38.5%. CONCLUSIONS: Chromosome 9 pericentric inversions did not result in unbalanced structural rearrangements in day 5/6 embryo samples, supporting that this population variant is not associated with increased reproductive risks.


Assuntos
Inversão Cromossômica/genética , Cromossomos Humanos Par 9/genética , Fertilização In Vitro , Diagnóstico Pré-Implantação , Adulto , Aneuploidia , Blastocisto/patologia , Hibridização Genômica Comparativa , Transferência Embrionária , Feminino , Testes Genéticos , Humanos , Idade Materna , Gravidez , Taxa de Gravidez , Fatores de Risco , Translocação Genética/genética
20.
Sci Rep ; 9(1): 16811, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727908

RESUMO

Vitamin C (VC) and vitamin D (VD) have been widely used as the dietary supplements and in treatment of diseases both independently and in combination. Whether there is a connection between their pathways is critical for their therapeutic applications. Using whole-genome expression profiles, we performed multiple measures of associations, networks, eQTL mappings and expressions of key genes of interest in VC and VD functions. Several key genes in their pathways were found to be associated. Gc and Rgn play important roles connecting VC and VD pathways in mice. The r values of expression levels between Gc and Rgn in mouse spleen, liver, lung, and kidney are 0.937, 0.558, 0.901, and 0.617, respectively. The expression QTLs of Gc and Rgn are mapped onto the same locations, i.e., 68-76 MB in chromosome 7 and 26-36 MB in chromosome 9. In humans, there are positive correlations between CYP27B1 and SLC23A1 expression levels in kidney (r = 0.733) and spleen (r = 0.424). SLC23A2 and RXRA are minimally associated in both mouse and human. These data indicate that pathways of VC and VD are not independent but affect each other, and this effect is different between mice and humans during VC and VD synthesis and transportation.


Assuntos
Ácido Ascórbico/metabolismo , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Locos de Características Quantitativas , Vitamina D/metabolismo , Sequenciamento Completo do Exoma/métodos , Animais , Transporte Biológico , Proteínas de Ligação ao Cálcio/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 9/genética , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Rim/química , Fígado/química , Pulmão/química , Camundongos , Especificidade de Órgãos , Baço/química , Proteína de Ligação a Vitamina D/genética
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