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1.
N Engl J Med ; 388(17): 1559-1571, 2023 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-37043637

RESUMEN

BACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).


Asunto(s)
Genómica , Enfermedades Raras , Niño , Humanos , Exoma , Irlanda/epidemiología , Reino Unido/epidemiología , Enfermedades Raras/diagnóstico , Enfermedades Raras/epidemiología , Enfermedades Raras/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Estudios de Asociación Genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/genética , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/genética , Facies , Trastornos de la Conducta Infantil/diagnóstico , Trastornos de la Conducta Infantil/genética , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética
2.
Hum Mutat ; 43(6): 682-697, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35143074

RESUMEN

DECIPHER (https://www.deciphergenomics.org) is a free web platform for sharing anonymized phenotype-linked variant data from rare disease patients. Its dynamic interpretation interfaces contextualize genomic and phenotypic data to enable more informed variant interpretation, incorporating international standards for variant classification. DECIPHER supports almost all types of germline and mosaic variation in the nuclear and mitochondrial genome: sequence variants, short tandem repeats, copy-number variants, and large structural variants. Patient phenotypes are deposited using Human Phenotype Ontology (HPO) terms, supplemented by quantitative data, which is aggregated to derive gene-specific phenotypic summaries. It hosts data from >250 projects from ~40 countries, openly sharing >40,000 patient records containing >51,000 variants and >172,000 phenotype terms. The rich phenotype-linked variant data in DECIPHER drives rare disease research and diagnosis by enabling patient matching within DECIPHER and with other resources, and has been cited in >2,600 publications. In this study, we describe the types of data deposited to DECIPHER, the variant interpretation tools, and patient matching interfaces which make DECIPHER an invaluable rare disease resource.


Asunto(s)
Bases de Datos Genéticas , Enfermedades Raras , Genómica , Humanos , Fenotipo , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Programas Informáticos
3.
Nucleic Acids Res ; 43(Database issue): D662-9, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25352552

RESUMEN

Ensembl (http://www.ensembl.org) is a genomic interpretation system providing the most up-to-date annotations, querying tools and access methods for chordates and key model organisms. This year we released updated annotation (gene models, comparative genomics, regulatory regions and variation) on the new human assembly, GRCh38, although we continue to support researchers using the GRCh37.p13 assembly through a dedicated site (http://grch37.ensembl.org). Our Regulatory Build has been revamped to identify regulatory regions of interest and to efficiently highlight their activity across disparate epigenetic data sets. A number of new interfaces allow users to perform large-scale comparisons of their data against our annotations. The REST server (http://rest.ensembl.org), which allows programs written in any language to query our databases, has moved to a full service alongside our upgraded website tools. Our online Variant Effect Predictor tool has been updated to process more variants and calculate summary statistics. Lastly, the WiggleTools package enables users to summarize large collections of data sets and view them as single tracks in Ensembl. The Ensembl code base itself is more accessible: it is now hosted on our GitHub organization page (https://github.com/Ensembl) under an Apache 2.0 open source license.


Asunto(s)
Bases de Datos de Ácidos Nucleicos , Genómica , Animales , Epigénesis Genética , Variación Genética , Genoma Humano , Humanos , Internet , Ratones , Anotación de Secuencia Molecular , Secuencias Reguladoras de Ácidos Nucleicos , Programas Informáticos
4.
Nucleic Acids Res ; 42(Database issue): D749-55, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24316576

RESUMEN

Ensembl (http://www.ensembl.org) creates tools and data resources to facilitate genomic analysis in chordate species with an emphasis on human, major vertebrate model organisms and farm animals. Over the past year we have increased the number of species that we support to 77 and expanded our genome browser with a new scrollable overview and improved variation and phenotype views. We also report updates to our core datasets and improvements to our gene homology relationships from the addition of new species. Our REST service has been extended with additional support for comparative genomics and ontology information. Finally, we provide updated information about our methods for data access and resources for user training.


Asunto(s)
Bases de Datos Genéticas , Genómica , Animales , Cordados/genética , Variación Genética , Humanos , Internet , Ratones , Anotación de Secuencia Molecular , Fenotipo , Ratas
5.
Hum Mutat ; 36(10): 941-9, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26220709

RESUMEN

DECIPHER (https://decipher.sanger.ac.uk) is a web-based platform for secure deposition, analysis, and sharing of plausibly pathogenic genomic variants from well-phenotyped patients suffering from genetic disorders. DECIPHER aids clinical interpretation of these rare sequence and copy-number variants by providing tools for variant analysis and identification of other patients exhibiting similar genotype-phenotype characteristics. DECIPHER also provides mechanisms to encourage collaboration among a global community of clinical centers and researchers, as well as exchange of information between clinicians and researchers within a consortium, to accelerate discovery and diagnosis. DECIPHER has contributed to matchmaking efforts by enabling the global clinical genetics community to identify many previously undiagnosed syndromes and new disease genes, and has facilitated the publication of over 700 peer-reviewed scientific publications since 2004. At the time of writing, DECIPHER contains anonymized data from ∼250 registered centers on more than 51,500 patients (∼18000 patients with consent for data sharing and ∼25000 anonymized records shared privately). In this paper, we describe salient features of the platform, with special emphasis on the tools and processes that aid interpretation, sharing, and effective matchmaking with other data held in the database and that make DECIPHER an invaluable clinical and research resource.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Difusión de la Información/métodos , Enfermedades Raras/genética , Bases de Datos Genéticas , Variación Genética , Humanos , Fenotipo , Programas Informáticos , Interfaz Usuario-Computador , Navegador Web
6.
Nucleic Acids Res ; 41(Database issue): D48-55, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23203987

RESUMEN

The Ensembl project (http://www.ensembl.org) provides genome information for sequenced chordate genomes with a particular focus on human, mouse, zebrafish and rat. Our resources include evidenced-based gene sets for all supported species; large-scale whole genome multiple species alignments across vertebrates and clade-specific alignments for eutherian mammals, primates, birds and fish; variation data resources for 17 species and regulation annotations based on ENCODE and other data sets. Ensembl data are accessible through the genome browser at http://www.ensembl.org and through other tools and programmatic interfaces.


Asunto(s)
Bases de Datos Genéticas , Genómica , Animales , Regulación de la Expresión Génica , Variación Genética , Humanos , Internet , Ratones , Anotación de Secuencia Molecular , Ratas , Programas Informáticos , Pez Cebra/genética
7.
Nucleic Acids Res ; 40(Database issue): D84-90, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22086963

RESUMEN

The Ensembl project (http://www.ensembl.org) provides genome resources for chordate genomes with a particular focus on human genome data as well as data for key model organisms such as mouse, rat and zebrafish. Five additional species were added in the last year including gibbon (Nomascus leucogenys) and Tasmanian devil (Sarcophilus harrisii) bringing the total number of supported species to 61 as of Ensembl release 64 (September 2011). Of these, 55 species appear on the main Ensembl website and six species are provided on the Ensembl preview site (Pre!Ensembl; http://pre.ensembl.org) with preliminary support. The past year has also seen improvements across the project.


Asunto(s)
Bases de Datos Genéticas , Genómica , Animales , Regulación de la Expresión Génica , Variación Genética , Humanos , Ratones , Anotación de Secuencia Molecular , Ratas
8.
Nucleic Acids Res ; 39(Database issue): D800-6, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21045057

RESUMEN

The Ensembl project (http://www.ensembl.org) seeks to enable genomic science by providing high quality, integrated annotation on chordate and selected eukaryotic genomes within a consistent and accessible infrastructure. All supported species include comprehensive, evidence-based gene annotations and a selected set of genomes includes additional data focused on variation, comparative, evolutionary, functional and regulatory annotation. The most advanced resources are provided for key species including human, mouse, rat and zebrafish reflecting the popularity and importance of these species in biomedical research. As of Ensembl release 59 (August 2010), 56 species are supported of which 5 have been added in the past year. Since our previous report, we have substantially improved the presentation and integration of both data of disease relevance and the regulatory state of different cell types.


Asunto(s)
Bases de Datos Genéticas , Genómica , Animales , Variación Genética , Humanos , Ratones , Anotación de Secuencia Molecular , Ratas , Secuencias Reguladoras de Ácidos Nucleicos , Programas Informáticos , Pez Cebra/genética
9.
Nucleic Acids Res ; 38(Database issue): D557-62, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19906699

RESUMEN

Ensembl (http://www.ensembl.org) integrates genomic information for a comprehensive set of chordate genomes with a particular focus on resources for human, mouse, rat, zebrafish and other high-value sequenced genomes. We provide complete gene annotations for all supported species in addition to specific resources that target genome variation, function and evolution. Ensembl data is accessible in a variety of formats including via our genome browser, API and BioMart. This year marks the tenth anniversary of Ensembl and in that time the project has grown with advances in genome technology. As of release 56 (September 2009), Ensembl supports 51 species including marmoset, pig, zebra finch, lizard, gorilla and wallaby, which were added in the past year. Major additions and improvements to Ensembl since our previous report include the incorporation of the human GRCh37 assembly, enhanced visualisation and data-mining options for the Ensembl regulatory features and continued development of our software infrastructure.


Asunto(s)
Biología Computacional/métodos , Bases de Datos Genéticas , Bases de Datos de Ácidos Nucleicos , Acceso a la Información , Animales , Biología Computacional/tendencias , Bases de Datos de Proteínas , Variación Genética , Genómica/métodos , Humanos , Almacenamiento y Recuperación de la Información/métodos , Internet , Estructura Terciaria de Proteína , Programas Informáticos , Especificidad de la Especie
10.
BMC Bioinformatics ; 11: 239, 2010 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-20459812

RESUMEN

BACKGROUND: The Ensembl web site has provided access to genomic information for almost 10 years. During this time the amount of data available through Ensembl has grown dramatically. At the same time, the World Wide Web itself has become a dramatically more important component of the scientific workflow and the way that scientists share and access data and scientific information. Since 2000, the Ensembl web interface has had three major updates and numerous smaller updates. These have largely been in response to expanding data types and valuable representations of existing data types. In 2007 it was realised that a radical new approach would be required in order to serve the project's future requirements, and development therefore focused on identifying suitable web technologies for implementation in the 2008 site redesign. RESULTS: By comparing the Ensembl website to well-known "Web 2.0" sites, we were able to identify two main areas in which cutting-edge technologies could be advantageously deployed: server efficiency and interface latency. We then evaluated the performance of the existing site using browser-based tools and Apache benchmarking, and selected appropriate technologies to overcome any issues found. Solutions included optimization of the Apache web server, introduction of caching technologies and widespread implementation of AJAX code. These improvements were successfully deployed on the Ensembl website in late 2008 and early 2009. CONCLUSIONS: Web 2.0 technologies provide a flexible and efficient way to access the terabytes of data now available from Ensembl, enhancing the user experience through improved website responsiveness and a rich, interactive interface.


Asunto(s)
Biología Computacional/métodos , Internet , Bases de Datos Factuales , Genoma , Programas Informáticos , Interfaz Usuario-Computador
11.
BMC Genomics ; 11: 293, 2010 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-20459805

RESUMEN

BACKGROUND: The maturing field of genomics is rapidly increasing the number of sequenced genomes and producing more information from those previously sequenced. Much of this additional information is variation data derived from sampling multiple individuals of a given species with the goal of discovering new variants and characterising the population frequencies of the variants that are already known. These data have immense value for many studies, including those designed to understand evolution and connect genotype to phenotype. Maximising the utility of the data requires that it be stored in an accessible manner that facilitates the integration of variation data with other genome resources such as gene annotation and comparative genomics. DESCRIPTION: The Ensembl project provides comprehensive and integrated variation resources for a wide variety of chordate genomes. This paper provides a detailed description of the sources of data and the methods for creating the Ensembl variation databases. It also explores the utility of the information by explaining the range of query options available, from using interactive web displays, to online data mining tools and connecting directly to the data servers programmatically. It gives a good overview of the variation resources and future plans for expanding the variation data within Ensembl. CONCLUSIONS: Variation data is an important key to understanding the functional and phenotypic differences between individuals. The development of new sequencing and genotyping technologies is greatly increasing the amount of variation data known for almost all genomes. The Ensembl variation resources are integrated into the Ensembl genome browser and provide a comprehensive way to access this data in the context of a widely used genome bioinformatics system. All Ensembl data is freely available at http://www.ensembl.org and from the public MySQL database server at ensembldb.ensembl.org.


Asunto(s)
Bases de Datos Genéticas , Variación Genética , Genómica/métodos , Algoritmos , Animales , Secuencia de Bases , Bovinos , Genotipo , Humanos , Internet , Desequilibrio de Ligamiento , Ratones , Fenotipo , Filogenia , Polimorfismo de Nucleótido Simple , Ratas , Análisis de Secuencia de ADN , Interfaz Usuario-Computador
12.
Artículo en Inglés | MEDLINE | ID: mdl-26896847

RESUMEN

Evolution provides the unifying framework with which to understand biology. The coherent investigation of genic and genomic data often requires comparative genomics analyses based on whole-genome alignments, sets of homologous genes and other relevant datasets in order to evaluate and answer evolutionary-related questions. However, the complexity and computational requirements of producing such data are substantial: this has led to only a small number of reference resources that are used for most comparative analyses. The Ensembl comparative genomics resources are one such reference set that facilitates comprehensive and reproducible analysis of chordate genome data. Ensembl computes pairwise and multiple whole-genome alignments from which large-scale synteny, per-base conservation scores and constrained elements are obtained. Gene alignments are used to define Ensembl Protein Families, GeneTrees and homologies for both protein-coding and non-coding RNA genes. These resources are updated frequently and have a consistent informatics infrastructure and data presentation across all supported species. Specialized web-based visualizations are also available including synteny displays, collapsible gene tree plots, a gene family locator and different alignment views. The Ensembl comparative genomics infrastructure is extensively reused for the analysis of non-vertebrate species by other projects including Ensembl Genomes and Gramene and much of the information here is relevant to these projects. The consistency of the annotation across species and the focus on vertebrates makes Ensembl an ideal system to perform and support vertebrate comparative genomic analyses. We use robust software and pipelines to produce reference comparative data and make it freely available. Database URL: http://www.ensembl.org.


Asunto(s)
Biología Computacional/métodos , Genoma , Genómica , Algoritmos , Animales , ADN Complementario/genética , Bases de Datos Genéticas , Evolución Molecular , Etiquetas de Secuencia Expresada , Humanos , Filogenia , Control de Calidad , ARN no Traducido/genética , Alineación de Secuencia , Análisis de Secuencia de ARN , Programas Informáticos
13.
Artículo en Inglés | MEDLINE | ID: mdl-26888907

RESUMEN

New experimental techniques in epigenomics allow researchers to assay a diversity of highly dynamic features such as histone marks, DNA modifications or chromatin structure. The study of their fluctuations should provide insights into gene expression regulation, cell differentiation and disease. The Ensembl project collects and maintains the Ensembl regulation data resources on epigenetic marks, transcription factor binding and DNA methylation for human and mouse, as well as microarray probe mappings and annotations for a variety of chordate genomes. From this data, we produce a functional annotation of the regulatory elements along the human and mouse genomes with plans to expand to other species as data becomes available. Starting from well-studied cell lines, we will progressively expand our library of measurements to a greater variety of samples. Ensembl's regulation resources provide a central and easy-to-query repository for reference epigenomes. As with all Ensembl data, it is freely available at http://www.ensembl.org, from the Perl and REST APIs and from the public Ensembl MySQL database server at ensembldb.ensembl.org. Database URL: http://www.ensembl.org.


Asunto(s)
Biología Computacional/métodos , ADN/análisis , Bases de Datos Genéticas , Secuencias de Aminoácidos , Animales , Metilación de ADN , Epigénesis Genética , Epigenómica , Genoma , Genoma Humano , Genómica , Histonas/química , Humanos , Ratones , Anotación de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos
15.
Eur J Appl Physiol ; 98(4): 363-72, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16960725

RESUMEN

The sport of rock climbing has increased in popularity and as a focus for research. Previous studies have examined the physiological determinants for successful performance. Variation is evident between studies over lactate sampling sites and assay methods. The aim of this study was to examine the limits of agreement between the YSI 2300 analyser and the Lactate Pro for finger and ear capillary blood samples in a climbing context. Forty-five (31 males and 14 females) participants volunteered to complete the climbing trial. Blood samples were collected simultaneously from finger and ear pre, post and 5 min post climb. The repeatability results indicated a good agreement across samples. Modelling analysis indicated the use of a -0.175 mmol l(-1) adjustment to move from Lactate Pro to YSI finger concentrations. To move from finger to ear concentrations, using the Lactate Pro, modelling analysis suggested a regression equation of Y = 0.827x + 0.769 adjustment for pre climb samples and Y = 0.955x + 0.566 for post climb concentrations. To better understand the physiological demands of climbing further research on natural rock is required. Results from this study suggest the Lactate Pro and blood sampling from the ear lobe could be of benefit to future rock climbing field studies.


Asunto(s)
Recolección de Muestras de Sangre/instrumentación , Recolección de Muestras de Sangre/métodos , Ejercicio Físico/fisiología , Ácido Láctico/sangre , Adulto , Oído Externo/irrigación sanguínea , Femenino , Dedos/irrigación sanguínea , Humanos , Masculino , Flujo Sanguíneo Regional/fisiología , Reproducibilidad de los Resultados
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