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1.
Mem. Inst. Oswaldo Cruz ; 116: e200517, 2021. tab, graf
Article in English | LILACS | ID: biblio-1154877

ABSTRACT

Molecular-typing can help in unraveling epidemiological scenarios and improvement for disease control strategies. A literature review of Mycobacterium tuberculosis transmission in Brazil through genotyping on 56 studies published from 1996-2019 was performed. The clustering rate for mycobacterial interspersed repetitive units - variable tandem repeats (MIRU-VNTR) of 1,613 isolates were: 73%, 33% and 28% based on 12, 15 and 24-loci, respectively; while for RFLP-IS6110 were: 84% among prison population in Rio de Janeiro, 69% among multidrug-resistant isolates in Rio Grande do Sul, and 56.2% in general population in São Paulo. These findings could improve tuberculosis (TB) surveillance and set up a solid basis to build a database of Mycobacterium genomes.


Subject(s)
Humans , Polymorphism, Restriction Fragment Length/genetics , Minisatellite Repeats/genetics , Mycobacterium tuberculosis/genetics , Brazil/epidemiology , Bacterial Typing Techniques , Molecular Epidemiology , Whole Genome Sequencing , Genotype , Mycobacterium tuberculosis/isolation & purification
2.
Article in English | WPRIM | ID: wpr-887737

ABSTRACT

Objective@#To evaluate multidrug resistant loop-mediated isothermal amplification (MDR-LAMP) assay for the early diagnosis of multidrug-resistant tuberculosis and to compare the mutation patterns associated with the @*Methods@#MDR-LAMP assay was evaluated using 100 @*Results@#The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MDR-LAMP were 85.5%, 93.6%, 96.7%, and 74.4% for the detection of resistance to isoniazid and rifampicin, respectively, and 80.5%, 92.3%, 98.6%, and 41.4% for the detection of @*Conclusion@#MDR-LAMP is a rapid and accessible assay for the laboratory identification of rifampicin and isoniazid resistance of


Subject(s)
Antitubercular Agents , Bacterial Proteins/genetics , Catalase/genetics , DNA, Bacterial/analysis , DNA-Directed RNA Polymerases/genetics , Drug Resistance, Multiple, Bacterial/genetics , Isoniazid , Molecular Diagnostic Techniques/methods , Mutation , Mycobacterium tuberculosis/isolation & purification , Nucleic Acid Amplification Techniques/methods , Oxidoreductases/genetics , Phenotype , Rifampin , Whole Genome Sequencing
4.
Article in Chinese | WPRIM | ID: wpr-879872

ABSTRACT

Pediatric patients in the neonatal intensive care unit (NICU) and the pediatric intensive care unit (PICU) have a high incidence rate of genetic diseases, and early rapid etiological diagnosis and targeted interventions can help to reduce mortality or improve prognosis. Whole-genome sequencing covers more comprehensive information including point mutation, copy number, and structural and rearrangement variations in the intron region and has become one of the powerful diagnostic tools for genetic diseases. Sequencing data require highly professional judgment and interpretation and are returned for clinical application after several weeks, which cannot meet the need for the diagnosis and treatment of genetic diseases in children. This article introduces the clinical application of rapid whole-genome sequencing in the NICU/PICU and briefly describes related techniques of artificial intelligence-rapid whole-genome sequencing diagnostic system, a rapid high-throughput automated platform for the diagnosis of genetic diseases. The diagnostic system introduces artificial intelligence into the processing of data after whole-genome sequencing and can solve the problems of long time and professional interpretation required for routine genome sequencing and provide a rapid diagnostic regimen for critically ill children suspected of genetic diseases within 24 hours, and therefore, it holds promise for clinical application.


Subject(s)
Artificial Intelligence , Child , Critical Illness , Humans , Infant, Newborn , Intensive Care Units, Neonatal , Intensive Care Units, Pediatric , Whole Genome Sequencing
5.
Article in Chinese | WPRIM | ID: wpr-879619

ABSTRACT

OBJECTIVE@#To study the correlation between DNA methylation patterns and gene expression in Down syndrome (DS).@*METHODS@#Induced pluripotent stem cells (iPSCs) derived from normal controls and DS patients were subjected to whole genome bisulfite sequencing and differentially methylated region (DMR) screening. Statistical analysis for chromosomal and gene element distribution were carried out for DMR. Gene ontology (GO) and enrichment-based cluster analysis were used to explore the molecular function of differentially expressed genes.@*RESULTS@#A total of 1569 DMR were identified in iPSCs derived from DS patients, for which the proportion of hypermethylation in promoter regions was significantly greater than that of the genebody. No DMR enrichment was noted on chromosome 21. Hypermethylation of the promoter and genebody was predicted to be inhibitory for gene expression. Functional clustering revealed the pathways related to neurodevelopmental, stem cell pluripotency and organ size regulation to be significantly correlated with differentially methylated genes.@*CONCLUSION@#Extensive and stochastic anomalies of genome-wide DNA methylation has been discovered in iPSCs derived from DS patients, for which the pattern and molecular regulation of methylation were significantly different from those of normal controls. Above findings suggested that DNA methylation pattern may play a vital role in both the pathogenesis of neurodevelopmental disorders and other phenotypic abnormalities during early embryonic development.


Subject(s)
DNA Methylation , Down Syndrome/genetics , Female , Humans , Induced Pluripotent Stem Cells , Pregnancy , Promoter Regions, Genetic , Whole Genome Sequencing
6.
Biosci. j. (Online) ; 36(6): 2020-2028, 01-11-2020. ilus, tab, graf
Article in English | LILACS | ID: biblio-1148292

ABSTRACT

Pseudomonas syringae pv. actinidiae is a bacterial pathogen of kiwifruit. Based on the results of the pathogenicity assay, we sequenced the strain Pseudomonas syringae (Psa3) P155 which possesses a series of virulence and resistance genes, CRISPR candidate elements, prophage related sequences, methylation modifications, genomic islands as well as one plasmid. Most importantly, the copper resistance genes copA, copB, copC, copD, and copZ as well as aminoglycoside resistance gene ksgA were identified in strain P155, which would pose a threat to kiwifruit production. The complete sequence we reported here will provide valuable information for a better understanding of the genetic structure and pathogenic characteristics of the genome of P155.


Pseudomonas syringae pv. actinidiae agente causal do cancro bacteriano do kiwi. Com base nos resultados do teste de patogenicidade, foi sequenciado um isolado de Pseudomonas syringae (Psa3) P155, que abriga a uma série de genes de virulência e resistência, elementos candidatos CRISPR, sequências relacionadas a profagos, modificações na metilação, ilhas genômicas, e também um plasmídeo. O mais importante foram os genes de resistência ao cobre, copA, copB, copC, copD e copZ, bem como, o gene de resistência aminoglicosídea ksgA identificados na estirpe P155, os quais representariam uma ameaça à produção de kiwi. A sequência completa relatada fornecerá informações valiosas para uma melhor compreensão da estrutura genética e as características patogênicas do genoma de P155.


Subject(s)
Virulence , Actinidia , Pseudomonas syringae , Whole Genome Sequencing
7.
Rev. cuba. hematol. inmunol. hemoter ; 36(3): e1243, jul.-set. 2020.
Article in Spanish | LILACS, CUMED | ID: biblio-1156443

ABSTRACT

Las neoplasias hematológicas se caracterizan por un gran número y complejidad de alteraciones genéticas, desde la formación de genes de fusión a partir de translocaciones e inversiones cromosómicas hasta mutaciones génicas y alteraciones epigenéticas que han permitido la identificación de nuevos oncogenes y genes supresores de tumores responsables de su etiología. Al abordar el estudio genético de las leucemias se utilizan múltiples técnicas como la citogenética convencional, citogenética molecular (hibridaciónin situ por fluorescencia (FISH), esta última con una mayor sensibilidad, especificidad y rapidez que permiten el diagnóstico, la estratificación pronóstica y seguimiento de la enfermedad. Las técnicas anteriores se integran con técnicas de biología molecular, secuenciación génica, entre otras, que permiten el hallazgo de nuevos marcadores genéticos con una mejor caracterización de las hemopatías malignas y la posibilidad del desarrollo de nuevos fármacos específicos que actúen sobre la diana molecular. El objetivo fue revisar la utilidad de la citogenética y la secuenciación génica en el estudio de la leucemia mieloide aguda y la leucemia linfocítica crónica. Ante las ventajas, desventajas y limitaciones de estas técnicas genéticas es necesario utilizarlas de forma complementaria y nunca excluyente(AU)


Hematological neoplasms are characterized by a large number and great complexity of genetic disorders, from the formation of fusion genes after chromosomal translocations and inversions to gene mutation and epigenetic disorders that have permitted the identification of new oncogenes and tumor-suppressing genes responsible for their etiology. When addressing the genetic study of leukemias, multiple techniques are used, such as conventional cytogenetics, molecular cytogenetics, and fluorescence in situ hybridization (FISH), the latter having the higher degree of sensitivity, specificity and speed, which allow diagnosis, prognostic stratification and follow-up of the disease. The previous techniques are integrated with molecular biology techniques, gene sequencing, among others, which allow discovery of new genetic markers with better characterization of malignant hemopathies and the possibility of developing new specific drugs against the molecular target. The objective was to review the usefulness of cytogenetics and gene sequencing in the study of acute myeloid leukemia and chronic lymphocytic leukemia. Given the advantages, disadvantages and limitations of these genetic techniques, it is necessary to use them in as complementary but never exclusive management ways(AU)


Subject(s)
Humans , Oncogenes , Genetic Markers , In Situ Hybridization, Fluorescence/methods , Hematologic Neoplasms/genetics , Cytogenetics , Epigenomics , Genetic Diseases, Inborn , Molecular Biology , Whole Genome Sequencing/methods
8.
Mem. Inst. Oswaldo Cruz ; 115: e200520, 2020. tab, graf
Article in English | LILACS | ID: biblio-1154871

ABSTRACT

BACKGROUND The evaluation of procedures for drug susceptibility prediction of Mycobacterium tuberculosis based on genomic data against the conventional reference method test based on culture is realistic considering the scenario of growing number of tools proposals based on whole-genome sequences (WGS). OBJECTIVES This study aimed to evaluate drug susceptibility testing (DST) outcome based on WGS tools and the phenotypic methods performed on isolates of M. tuberculosis Lineage 1 from the state of Pará, Brazil, generally associated with low levels of drug resistance. METHODOLOGY Culture based DST was performed using the Proportion Method in Löwenstein-Jensen medium on 71 isolates that had been submitted to WGS. We analysed the seven main genome sequence-based tools for resistance and lineage prediction applied to M. tuberculosis and for comparison evaluation we have used the Kappa concordance test. FINDINGS When comparing the WGS-based tools against the DST, we observed the highest level of agreement using TB-profiler. Among the tools, TB-profiler, KvarQ and Mykrobe were those which identified the largest number of TB-MDR cases. Comparing the four most sensitive tools regarding resistance prediction, agreement was observed for 43 genomes. MAIN CONCLUSIONS Drug resistance profiling using next-generation sequencing offers rapid assessment of resistance-associated mutations, therefore facilitating rapid access to effective treatment.


Subject(s)
Humans , Tuberculosis, Multidrug-Resistant/genetics , Drug Resistance, Multiple, Bacterial/genetics , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/genetics , Antitubercular Agents/pharmacology , Brazil , Pharmaceutical Preparations , Microbial Sensitivity Tests , Tuberculosis, Multidrug-Resistant/drug therapy , Drug Resistance, Multiple, Bacterial/drug effects , Whole Genome Sequencing , Mycobacterium tuberculosis/isolation & purification , Antitubercular Agents/therapeutic use
9.
Biol. Res ; 53: 21, 2020. tab, graf
Article in English | LILACS | ID: biblio-1124206

ABSTRACT

BACKGROUND: Liriodendron chinense ranges widely in subtropical China and northern Vietnam; however, it inhabits several small, isolated populations and is now an endangered species due to its limited seed production. The objective of this study was to develop a set of nuclear SSR (simple sequence repeats) and multiple chloroplast genome markers for genetic studies in L. chinense and their characterization in diverse germplasm. RESULTS: We performed low-coverage whole genome sequencing of the L. chinense from four genotypes, assembled the chloroplast genome and identified nuclear SSR loci by searching in contigs for SSR motifs. Comparative analysis of the four chloroplast genomes of L. chinense revealed 45 SNPs, 17 indels, 49 polymorphic SSR loci, and five small inversions. Most chloroplast intraspecific polymorphisms were located in the interspaces of single-copy regions. In total, 6147 SSR markers were isolated from low-coverage whole genome sequences. The most common SSR motifs were dinucleotide (70.09%), followed by trinucleotide motifs (23.10%). The motif AG/TC (33.51%) was the most abundant, followed by TC/AG (25.53%). A set of 13 SSR primer combinations were tested for amplification and their ability to detect polymorphisms in a set of 109 L. chinense individuals, representing distinct varieties or germplasm. The number of alleles per locus ranged from 8 to 28 with an average of 21 alleles. The expected heterozygosity (He) varied from 0.19 to 0.93 and the observed heterozygosity (Ho) ranged from 0.11 to 0.79. CONCLUSIONS: The genetic resources characterized and tested in this study provide a valuable tool to detect polymorphisms in L. chinense for future genetic studies and breeding programs.


Subject(s)
Polymorphism, Genetic/genetics , Genome, Plant/genetics , Liriodendron/genetics , Genome, Chloroplast/genetics , DNA Primers/genetics , DNA, Plant/genetics , Microsatellite Repeats , Alleles , Whole Genome Sequencing , Genotype
10.
Article in English | WPRIM | ID: wpr-880486

ABSTRACT

Scutellaria baicalensis (S. baicalensis) and Scutellaria barbata (S. barbata) are common medicinal plants of the Lamiaceae family. Both produce specific flavonoid compounds, including baicalein, scutellarein, norwogonin, and wogonin, as well as their glycosides, which exhibit antioxidant and antitumor activities. Here, we report chromosome-level genome assemblies of S. baicalensis and S. barbata with quantitative chromosomal variation (2n = 18 and 2n = 26, respectively). The divergence of S. baicalensis and S. barbata occurred far earlier than previously reported, and a whole-genome duplication (WGD) event was identified. The insertion of long terminal repeat elements after speciation might be responsible for the observed chromosomal expansion and rearrangement. Comparative genome analysis of the congeneric species revealed the species-specific evolution of chrysin and apigenin biosynthetic genes, such as the S. baicalensis-specific tandem duplication of genes encoding phenylalanine ammonia lyase and chalcone synthase, and the S. barbata-specific duplication of genes encoding 4-CoA ligase. In addition, the paralogous duplication, colinearity, and expression diversity of CYP82D subfamily members revealed the functional divergence of genes encoding flavone hydroxylase between S. baicalensis and S. barbata. Analyzing these Scutellaria genomes reveals the common and species-specific evolution of flavone biosynthetic genes. Thus, these findings would facilitate the development of molecular breeding and studies of biosynthesis and regulation of bioactive compounds.


Subject(s)
Evolution, Molecular , Flavonoids/biosynthesis , Genome, Plant , Plant Extracts/genetics , Scutellaria/metabolism , Whole Genome Sequencing
11.
Article in Spanish | LILACS | ID: biblio-1102169

ABSTRACT

La tecnología diagnóstica conocida como NGS por sus siglas en inglés, o Secuenciación de nueva generación, es relativamente nueva, y se está implementando en algunos hospitales de Panamá. Esta tecnología ha demostrado ser una herramienta muy eficiente para la detección de alteraciones genómicas o exómicas, tanto para la clínica como para la investigación. Dada la complejidad de esta prueba, requiere una infraestructura y un número importante de recursos humanos capacitados para poder implementar esta prueba. El propósito de este documento es establecer un marco de referencia para los procedimientos administrativos en cuanto a la realización de las pruebas de secuenciación por metodología NGS. Además, que el mismo sirva de guía para el establecimiento adecuado de programas internos de control y evaluación de calidad de esta tecnología en nuestro país y la región


The technology known as Next­Generation sequencing is relatively new, and it is been implemented in some Panamanian hospitals. It has demonstrated to be a very efficient tool to identify genomic and exomic variants in a clinical setting, as well for research purposes. Because of its complexity, it requires an important infrastructure and a significant number of trained health­care professionals to carry out this test. The purpose of this document is to establish a frame for the administrative and tec hnical aspects for NGS in a clinical setting. Moreover, it will serve as a guide to establish quality control procedures that the technology requires in our country and the region.


Subject(s)
Organization and Administration/standards , Molecular Biology/organization & administration , Kinetics , Databases, Nucleic Acid , Pathology, Molecular , Whole Genome Sequencing , Access to Essential Medicines and Health Technologies
12.
Appl. cancer res ; 39: 1-6, 2019. ilus, tab
Article in English | LILACS, Inca | ID: biblio-1006568

ABSTRACT

Background: Detection of somatic mutations is a mandatory practice for therapeutic definition in precision oncology. However, somatic mutation detection protocols use DNA from formalin-fixed and paraffin-embedded (FFPE) tumor tissues, which can result in detection of nonreproducible sequence artifacts, especially C:G > T:A transitions, in DNA. In recent studies, DNA pretreatment with uracil DNA glycosylase (UDG), an enzyme involved in base excision repair, significantly reduced the number of DNA artifacts after mutation detection by next-generation sequencing (NGS) and other methods, without affecting the capacity to detect real mutations. This study aimed to evaluate the effects of UDG enzymatic pretreatment in reducing the number of DNA sequencing artifacts from FFPE tumor samples, to improve the accuracy of genetic testing in the molecular diagnostic routine. Methods: We selected 12 FFPE tumor samples (10 melanoma, 1 lung, and 1 colorectal tumor sample) with different storage times. We compared sequencing results of a 16-hotspot gene panel of NGS libraries prepared with UDG-treated and untreated samples. Results: All UDG-treated samples showed large reductions in the total number of transitions (medium reduction of 80%) and the transition/transversion ratio (medium reduction of 75%). In addition, most sequence artifacts presented a low variant allele frequency (VAF < 10%) which are eliminated with UDG treatment. Conclusion: Including UDG enzymatic treatment before multiplex amplification in the NGS workflow significantly decreased the number of artifactual variants detected in FFPE samples. Thus, including this additional step in the current methodology should improve the rate of true mutation detection in the molecular diagnostic routine.


Subject(s)
Humans , Pain Measurement , Paraffin Embedding , Diagnostic Tests, Routine , Uracil-DNA Glycosidase , Whole Genome Sequencing
13.
Chinese Journal of Biotechnology ; (12): 2284-2294, 2019.
Article in Chinese | WPRIM | ID: wpr-781638

ABSTRACT

With the development of liquid biopsy technology, plasma cell-free DNA (cfDNA) becomes one of the research hotspots. Whole-genome bisulfite sequencing of plasma cell-free DNA has shown great potential medical applications such as cancer detection. However, the practical stability evaluation is still lacking. In this study, plasma cell-free DNA samples from two volunteers at different time were collected and prepared for sequencing in multiple laboratories. The library preparation strategies include pre-bisulfite, post-bisulfite and regular whole-genome sequencing. We established a set of quality control references for plasma cell-free DNA sequencing data and evaluated practical stability of blood collection, DNA extraction, and library preparation and sequencing depth. This work provided a technical practice guide for the application of plasma cfDNA methylation sequencing for clinical applications.


Subject(s)
Cell-Free Nucleic Acids , DNA Methylation , High-Throughput Nucleotide Sequencing , Humans , Sequence Analysis, DNA , Sulfites , Whole Genome Sequencing
14.
Article in Chinese | WPRIM | ID: wpr-781324

ABSTRACT

OBJECTIVE@#To apply high-throughput whole genome sequencing (WGS) and short tandem repeat (STR) typing to detect aneuploidies, heteroploidies and copy number variations(CNVs) in spontaneous abortic tissues.@*METHODS@#Chorionic villus samples from 145 patients with spontaneous abortion were subjected to detection of aneuploidies, heteroploidies and copy number variations by WGS and STR typing.@*RESULTS@#All testing was successful and the rate of chromosomal abnormalities among the patients was 22.07%. Among these, there were 11 trisomies, 3 monosomies, 2 triploidies, 5 autosomal mosaicisms, 4 sex chromosomal mosaicisms, 7 structural abnormalities (including 1 mosaicism). In 89 cases, there were 130 CNVs of uncertain significance, 47 likely benign CNVs, and 2 loss of one copy of pathogenic AR gene. One sample contained 6 fragment duplications and deletions. Only 24 samples had no abnormal finding.@*CONCLUSION@#The most important reason for spontaneous abortions is embryonic chromosomal abnormality. Combined STR typing and WGS is both comprehensive and fast, and may become a major means for the detection of chorionic villi tissue from spontaneous abortions.


Subject(s)
Abortion, Spontaneous , Genetics , Chorea , Genetics , Chromosome Aberrations , DNA Copy Number Variations , Female , Humans , Microsatellite Repeats , Pregnancy , Whole Genome Sequencing
15.
Article in English | WPRIM | ID: wpr-772945

ABSTRACT

Emerging antibiotic resistance is a major global health threat. The analysis of nucleic acid sequences linked to susceptibility phenotypes facilitates the study of genetic antibiotic resistance determinants to inform molecular diagnostics and drug development. We collected genetic data (11,087 newly-sequenced whole genomes) and culture-based resistance profiles (10,991 out of the 11,087 isolates comprehensively tested against 22 antibiotics in total) of clinical isolates including 18 main species spanning a time period of 30 years. Species and drug specific resistance patterns were observed including increased resistance rates for Acinetobacter baumannii to carbapenems and for Escherichia coli to fluoroquinolones. Species-level pan-genomes were constructed to reflect the genetic repertoire of the respective species, including conserved essential genes and known resistance factors. Integrating phenotypes and genotypes through species-level pan-genomes allowed to infer gene-drug resistance associations using statistical testing. The isolate collection and the analysis results have been integrated into GEAR-base, a resource available for academic research use free of charge at https://gear-base.com.


Subject(s)
Acinetobacter baumannii , Genetics , Bacteria , Genetics , Cell Culture Techniques , Methods , Drug Resistance, Microbial , Genetics , Escherichia coli , Genetics , Genome, Bacterial , Genotype , Humans , Internet , Microbial Sensitivity Tests , Phenotype , Whole Genome Sequencing
16.
Chinese Journal of Biotechnology ; (12): 541-557, 2019.
Article in Chinese | WPRIM | ID: wpr-771354

ABSTRACT

The emergence and spread of antimicrobial resistance has become a serious global issue. Bacterial characteristics, such as antimicrobial resistance genes, virulence-associated genes, plasmid types, and phylogenetic relationship among different strains, are the keys to unravel the occurrence and dissemination of antimicrobial resistance. However, the accuracy and efficiency of the traditional techniques, such as polymerase chain reaction and pulsed field gel electrophoresis is insufficient to underlying the mystery of antimicrobial resistance. Recently, the whole genome sequencing and high-throughput bioinformatics analysis have been successfully used in antimicrobial resistance studies, helping scientists to obtain the nature of antimicrobial resistance bacteria quickly, and more precisely to paint the evolutionary relationship among different strains. Therefore, in this study, we aim to systematically introduce the recent development of whole genome sequencing analysis, including different methods and corresponding characteristics of library preparation, platform sequencing, data analysis, and the latest application of the technology in the antimicrobial resistance research. We hope that this review can provide more comprehensive knowledge about whole genome sequencing and bioinformatic analysis for antimicrobial resistance research.


Subject(s)
Anti-Bacterial Agents , Computational Biology , Drug Resistance, Bacterial , Genome, Bacterial , Phylogeny , Whole Genome Sequencing
17.
Article in Chinese | WPRIM | ID: wpr-775762

ABSTRACT

OBJECTIVE@#To explore the genetic basis of cerebral palsy (CP).@*METHODS@#A pair of twins with cerebral palsy and different phenotypes were subjected to whole genome sequencing, and other 8 children with CP were subjected to whole exome sequencing. Genetic variations were screened by a self-designed filtration process in order to explore the CP-related biological pathways and genes.@*RESULTS@#Three biological pathways related to CP were identified, which included axon guiding, transmission across chemical synapses and protein-protein interactions at synapses, and 25 susceptibility genes for CP were identified.@*CONCLUSION@#The molecular mechanism of CP has been explored, which may provide clues for development of new treatment for CP.


Subject(s)
Cerebral Palsy , Genetics , Child , Genetic Testing , Humans , Phenotype , Whole Exome Sequencing , Whole Genome Sequencing
18.
Rev. colomb. cardiol ; 25(4): 264-276, jul.-ago. 2018. tab, graf
Article in Spanish | LILACS, COLNAL | ID: biblio-985469

ABSTRACT

Resumen Las cardiopatías familiares son un grupo de enfermedades con alta heterogeneidad clínica y genética. Debido a que pueden heredarse y a su asociación con la muerte súbita, se recomienda efectuar un estudio clínico y genético del individuo afectado y su familia a través de una unidad especializada. Con la implementación de la secuenciación masiva se ha facilitado el acceso a los estudios genéticos en la práctica clínica de forma más rutinaria. Sin embargo, dada la gran cantidad de información obtenida se hacen necesarios el análisis y la interpretación adecuada de los resultados para garantizar un diagnóstico correcto. Este nuevo modelo de medicina amplía nuestra comprensión sobre estas patologías, gracias a que optimiza el diagnóstico, da una mejor aproximación pronóstica de los pacientes e identifica individuos asintomáticos en riesgo. Este artículo pretende realizar una revisión de la arquitectura genética de las enfermedades cardíacas hereditarias y proporcionar un enfoque práctico acerca de la utilidad de la Medicina genómica en el diagnóstico, la estratificación del riesgo y el estudio familiar en pacientes con este tipo de patologías.


Abstract The familial heart diseases are a group of diseases with high clinical and genomic heterogeneity. As they can be inherited and are associated with sudden death, it is recommended to perform a clinical and genetic study of the individual affected, as well as the family, in a specialised unit. The implementation of massive sequencing has meant that access to genetic studies is available in the most routine clinical practice. However, due to the large amount of information obtained, the results have to analysed and interpreted to ensure a correct diagnosis. This new medicine model widens the understanding of these diseases, as due to the diagnosis being optimised, it provides a more accurate prognosis for the patients, and identifies asymptomatic individuals at risk. A review is presented on the genetic architecture of heritable heart disease and provides a practical approach on the usefulness of Genomic Medicine in the diagnosis, risk stratification, and the familial study in patients with these types of heart diseases.


Subject(s)
Humans , Death, Sudden, Cardiac , Cardiomyopathies , Phenotype , Whole Genome Sequencing , Genotype
19.
São Paulo; s.n; 2018. 127 p. ilus, tab, quadros.
Thesis in Portuguese | LILACS, Inca | ID: biblio-1015262

ABSTRACT

A Síndrome de Li Fraumeni (LFS) tem caráter autossômico dominante associada ao risco aumentado de câncer hereditário. Embora rara no mundo, no Brasil é frequente devido à ocorrência de uma mutação fundadora, a p.R337H TP53. A ocorrência de câncer e a idade de acometimento são variáveis mesmo em portadores da mesma mutação. Pacientes com mutações no gene TP53 podem desenvolver um amplo espectro de tumores, incluindo o carcinoma adrenocortical (ADR). Os mecanismos moleculares envolvidos na carcinogênese adrenocortical assim como os dados epidemiológicos associados a estes tumores são pouco explorados em literatura. Neste estudo, foram coletados e analisados os dados epidemiológicos dos ADR incluindo os efeitos de idade, período e coorte utilizando o banco de dados SEER, o qual reúne dados de 18 registros de câncer de base populacional dos EUA. Foi avaliado o perfil de alterações genômicas (CytoScan HD Array, Affymetrix) em ADR de pacientes com e sem a mutação p.R337H. Foi também comparado o perfil mutacional (sequenciamento do genoma) de três pacientes (tumor e tecido normal de 2 adultos e 1 criança) com ADR portadores da mutação TP53 p.R337H. Entre os casos de ADR diagnosticados nos EUA, aproximadamente 80% ocorreram após a quarta década de vida. Nas análises de sobrevida, houve diferença estatística (p<0,05) para gênero, com uma melhor sobrevida para as mulheres. Pacientes diagnosticados até os 19 anos e com doença localizada apresentaram uma sobrevida maior. A análise genômica em sete casos revelou 644 alterações. Os três casos positivos para a mutação p.R337H apresentaram 175 alterações genômicas (127 ganhos, 27 cnLOH e 21 perdas). Os quatros casos negativos para a mutação apresentaram 469 alterações (326 ganhos, 63 cnLOH e 80 perdas). Apesar do pequeno número amostral, os casos ADR positivos para a mutação TP53 p.R337H apresentaram um baixo nível de instabilidade genômica quando comparados com os casos não mutados. A análise de sequenciamento do genoma revelou alterações em genes previamente associados o ADR (como TP53, CTNNB1 e ATRX). Foram identificadas alterações em cinco genes com potencial associação ao desenvolvimento do ADR: HBB, MSR1, SH3TC2, LSS e ABCA4. Apesar do pequeno número amostral, foram identificados novos genes que podem estar associados ao ADR, no entanto esses achados deverão ser confirmados em estudos conduzidos em um grupo amostral maior (AU)


Li-Fraumeni syndrome (LFS) is an autosomal dominant disease with high risk to develop hereditary tumors. Although LFS is a worldwide rare disorder, in Brazil its incidence is higher due to the occurrence of a founder mutation, TP53 p.R337H. The cancer occurrence and age of onset are variable even considering patients with the same mutation. Patients carrying TP53 mutations can develop a large spectrum of tumors, including the adrenocortical carcinoma (ADR). The main molecular mechanisms and the epidemiological factors associated with these tumors are poorly explored in literature. In this study, epidemiological data of ADR were collected and analyzed, including the effects of age, period and cohort. The SEER database, which collects and publishes cancer incidence and survival data from 18 cancer registries from the USA, was used for this analysis. The genomic profile (CytoScan HD Array, Affymetrix) of ADR positive or negative for TP53 p.R337H was also investigated. Furthermore, the mutational profile (Whole Genome Sequencing- WGS) of three ADR patients (normal and tumor samples - 2 adults and 1 pediatric case), all of them positive for TP53 p.R337H mutation, were analyzed. Approximately 80% of the ADR cases diagnosed in the USA developed after the fourth decade of life. In the survival analyses, a statistical difference (p <0.05) was observed for gender, with women showing better survival. Patients diagnosed up to the age of 19 and with localized disease presented better survival. The genomic analysis of seven cases revealed 644 genomic alterations. The three TP53 p.R337H positive cases showed 175 genomic alterations (127 gains, 27 cnLOH and 21 losses). The four negative mutated cases presented 469 alterations (369 gains, 63 cnLOH and 80 losses). Despite the small set of samples, mutated cases presented lower level of chromosome instability compared to cases not carrying this mutation. The WGS analysis identified alterations in genes previously associated with ADR (as TP53, CTNNB1 and ATRX). In addition, five genes (HBB, MSR1, SH3TC2, LSS and ABCA4) potentially associated with the development of ADR were identified. This study revealed new genes that might be associated with ADR. However, further analysis are necessary in a larger number of samples to confirm our findings (AU)


Subject(s)
Male , Female , Infant , Child, Preschool , Child , Adolescent , Adult , Middle Aged , Neoplastic Syndromes, Hereditary , Li-Fraumeni Syndrome , Adrenocortical Carcinoma , Whole Genome Sequencing
20.
Frontiers of Medicine ; (4): 23-33, 2018.
Article in English | WPRIM | ID: wpr-772731

ABSTRACT

Two decades have passed since the first bacterial whole-genome sequencing, which provides new opportunity for microbial genome. Consequently, considerable genetic diversity encoded by bacterial genomes and among the strains in the same species has been revealed. In recent years, genome sequencing techniques and bioinformatics have developed rapidly, which has resulted in transformation and expedited the application of strategy and methodology for bacterial genome comparison used in dissection of infectious disease epidemics. Bacterial whole-genome sequencing and bioinformatic computing allow genotyping to satisfy the requirements of epidemiological study in disease control. In this review, we outline the significance and summarize the roles of bacterial genome sequencing in the context of bacterial disease control and prevention.We discuss the applications of bacterial genome sequencing in outbreak detection, source tracing, transmission mode discovery, and new epidemic clone identification. Wide applications of genome sequencing and data sharing in infectious disease surveillance networks will considerably promote outbreak detection and early warning to prevent the dissemination of bacterial diseases.


Subject(s)
Bacteria , Genetics , Bacterial Infections , Epidemiology , Microbiology , Bacterial Typing Techniques , Disease Outbreaks , Genome, Bacterial , Genotype , Humans , Population Surveillance , Whole Genome Sequencing
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