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1.
Nat Genet ; 39(4): 433-6, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17392799

ABSTRACT

Lists of variations in genomic DNA and their effects have been kept for some time and have been used in diagnostics and research. Although these lists have been carefully gathered and curated, there has been little standardization and coordination, complicating their use. Given the myriad possible variations in the estimated 24,000 genes in the human genome, it would be useful to have standard criteria for databases of variation. Incomplete collection and ascertainment of variants demonstrates a need for a universally accessible system. These and other problems led to the World Heath Organization-cosponsored meeting on June 20-23, 2006 in Melbourne, Australia, which launched the Human Variome Project. This meeting addressed all areas of human genetics relevant to collection of information on variation and its effects. Members of each of eight sessions (the clinic and phenotype, the diagnostic laboratory, the research laboratory, curation and collection, informatics, relevance to the emerging world, integration and federation and funding and sustainability) developed a number of recommendations that were then organized into a total of 96 recommendations to act as a foundation for future work worldwide. Here we summarize the background of the project, the meeting and its recommendations.


Subject(s)
Genome, Human , Guidelines as Topic , Polymorphism, Genetic , Genetic Diseases, Inborn/classification , Genetic Diseases, Inborn/genetics , Human Genome Project , Humans , World Health Organization
2.
Hum Mutat ; 35(12): 1476-84, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25219341

ABSTRACT

Mitochondrial DNA (mtDNA) is replicated throughout life in postmitotic cells, resulting in higher levels of somatic mutation than in nuclear genes. However, controversy remains as to the importance of low-level mtDNA somatic mutants in cancerous and normal human tissues. To capture somatic mtDNA mutations for functional analysis, we generated synaptosome cybrids from synaptic endings isolated from fresh hippocampus and cortex brain biopsies. We analyzed the whole mtDNA genome from 120 cybrid clones derived from four individual donors by chemical cleavage of mismatch and Sanger sequencing, scanning around two million base pairs. Seventeen different somatic point mutations were identified, including eight coding region mutations, four of which result in frameshifts. Examination of one cybrid clone with a novel m.2949_2953delCTATT mutation in MT-RNR2 (which encodes mitochondrial 16S rRNA) revealed a severe disruption of mtDNA-encoded protein translation. We also performed functional studies on a homoplasmic nonsense mutation in MT-ND1, previously reported in oncocytomas, and show that both ATP generation and the stability of oxidative phosphorylation complex I are disrupted. As the mtDNA remains locked against direct genetic manipulation, we demonstrate that the synaptosome cybrid approach can capture biologically relevant mtDNA mutants in vitro to study effects on mitochondrial respiratory chain function.


Subject(s)
Brain/metabolism , DNA, Mitochondrial/genetics , Oxidative Phosphorylation , Point Mutation , Synaptosomes/metabolism , Adenosine Triphosphate/biosynthesis , Amino Acid Sequence , Humans , Molecular Sequence Data
3.
Pediatr Nephrol ; 29(6): 971-7, 2014 Jun.
Article in English | MEDLINE | ID: mdl-23720012

ABSTRACT

X-linked Alport syndrome is a form of progressive renal failure caused by pathogenic variants in the COL4A5 gene. More than 700 variants have been described and a further 400 are estimated to be known to individual laboratories but are unpublished. The major genetic testing laboratories for X-linked Alport syndrome worldwide have established a Web-based database for published and unpublished COL4A5 variants ( https://grenada.lumc.nl/LOVD2/COL4A/home.php?select_db=COL4A5 ). This conforms with the recommendations of the Human Variome Project: it uses the Leiden Open Variation Database (LOVD) format, describes variants according to the human reference sequence with standardized nomenclature, indicates likely pathogenicity and associated clinical features, and credits the submitting laboratory. The database includes non-pathogenic and recurrent variants, and is linked to another COL4A5 mutation database and relevant bioinformatics sites. Access is free. Increasing the number of COL4A5 variants in the public domain helps patients, diagnostic laboratories, clinicians, and researchers. The database improves the accuracy and efficiency of genetic testing because its variants are already categorized for pathogenicity. The description of further COL4A5 variants and clinical associations will improve our ability to predict phenotype and our understanding of collagen IV biochemistry. The database for X-linked Alport syndrome represents a model for databases in other inherited renal diseases.


Subject(s)
Collagen Type IV/genetics , Databases, Nucleic Acid , Nephritis, Hereditary/genetics , Humans , Phenotype
4.
Hum Mutat ; 34(7): 927-36, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23559577

ABSTRACT

In about 20%-30% of phenylketonuria (PKU) patients (all phenotypes of PAH deficiency), Phe levels may be controlled through phenylalanine hydroxylase cofactor tetrahydrobiopterin therapy. These patients can be diagnosed by an oral tetrahydrobiopterin challenge and are characterized by mutations coding for proteins with substantial residual PAH activity. They can be treated with a commercially available synthetic form of tetrahydrobiopterin, either as a monotherapy or as adjunct to the diet. This review article summarizes molecular and metabolic bases of PKU and the importance of the tetrahydrobiopterin loading test used for PKU patients. On the basis of in vitro residual PAH activity, more than 1,200 genotypes from patients challenged with tetrahydrobiopterin were categorized as predictive for tetrahydrobiopterin responsiveness or non-responsiveness and correlated with the loading test, phenotype, and residual in vitro PAH activity. The coexpression of two distinct PAH mutant alleles revealed possible dominance effects (positive or negative) by one of the mutations on residual activity as result of interallelic complementation. The treatment of the transfected cells with tetrahydrobiopterin showed an increase in residual PAH activity with several mutations coexpressed.


Subject(s)
Biopterins/analogs & derivatives , Phenylalanine Hydroxylase/genetics , Phenylketonurias/drug therapy , Biopterins/pharmacology , Biopterins/therapeutic use , Genotype , Humans , Models, Molecular , Mutation , Phenylalanine Hydroxylase/chemistry , Phenylalanine Hydroxylase/drug effects , Phenylketonurias/diagnosis , Phenylketonurias/physiopathology , Treatment Outcome
5.
J Med Genet ; 49(4): 284-9, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22499349

ABSTRACT

The Human Variome Project Beijing Meeting, a joint meeting of the Human Variome Project Consortium and the Human Variome Project Chinese Node, was held in Beijing, 8th-12th of December, 2011. The aim of the Human Variome Project is to ensure that all information on genetic variation can be collected, curated, interpreted and shared freely and openly. The meeting officially welcomed the Human Variome Project Chinese Node as a partner of the Human Variome Project and focused on those areas where collaborations between China and the global Human Variome Project Consortium are required to develop and extend the coverage of international gene/disease specific databases.


Subject(s)
Genetic Variation , Human Genome Project , Cooperative Behavior , Databases, Genetic , Humans
6.
Hum Mutat ; 33(2): 298-305, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22052659

ABSTRACT

Information about genetic variation has been collected for some 20 years into registries, known as locus specific databases (LSDBs), which nowadays often contain information in addition to the actual genetic variation. Several issues have to be taken into account when considering establishing and maintaining LSDBs and these have been discussed previously in a number of articles describing guidelines and recommendations. This information is widely scattered and, for a newcomer, it would be difficult to obtain the latest information and guidance. Here, a sequence of steps essential for establishing an LSDB is discussed together with guidelines for each step. Curators need to collect information from various sources, code it in systematic way, and distribute to the research and clinical communities. In doing this, ethical issues have to be taken into account. To facilitate integration of information to, for example, analyze genotype-phenotype correlations, systematic data representation using established nomenclatures, data models, and ontologies is essential. LSDB curation and maintenance comprises a number of tasks that can be managed by following logical steps. These resources are becoming ever more important and new curators are essential to ensure that we will have expertly curated databases for all disease-related genes in the near future.


Subject(s)
Databases, Genetic/standards , Genetic Loci , Computational Biology/methods , Computational Biology/standards , Database Management Systems , Databases, Genetic/ethics , Documentation , Genes , Genetic Association Studies , Guidelines as Topic , Humans , Information Dissemination
7.
Hum Mutat ; 33(11): 1513-9, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22753370

ABSTRACT

The Human Variome Project (http://www.humanvariomeproject.org) is an international effort aiming to systematically collect and share information on all human genetic variation. The two main pillars of this effort are gene/disease-specific databases and a network of Human Variome Project Country Nodes. The latter are nationwide efforts to document the genomic variation reported within a specific population. The development and successful operation of the Human Variome Project Country Nodes are of utmost importance to the success of Human Variome Project's aims and goals because they not only allow the genetic burden of disease to be quantified in different countries, but also provide diagnosticians and researchers access to an up-to-date resource that will assist them in their daily clinical practice and biomedical research, respectively. Here, we report the discussions and recommendations that resulted from the inaugural meeting of the International Confederation of Countries Advisory Council, held on 12th December 2011, during the 2011 Human Variome Project Beijing Meeting. We discuss the steps necessary to maximize the impact of the Country Node effort for developing regional and country-specific clinical genetics resources and summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects.


Subject(s)
Genetic Variation , Genome, Human , Human Genome Project , Guidelines as Topic , Human Genome Project/economics , Human Genome Project/ethics , Human Genome Project/legislation & jurisprudence , Humans , International Cooperation , Registries , Software
8.
Hum Genomics ; 5(3): 141-55, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21504866

ABSTRACT

DNA mutation data currently reside in many online databases, which differ markedly in the terminology used to describe or define the mutation and also in completeness of content, potentially making it difficult both to locate a mutation of interest and to find sought-after data (eg phenotypic effect). To highlight the current deficiencies in the accessibility of web-based genetic variation information, we examined the ease with which various resources could be interrogated for five model mutations, using a set of simple search terms relating to the change in amino acid or nucleotide. Fifteen databases were investigated for the time and/or number of mouse clicks; clicks required to find the mutations; availability of phenotype data; the procedure for finding information; and site layout. Google and PubMed were also examined. The three locus-specific databases (LSDBs) generally yielded positive outcomes, but the 12 genome-wide databases gave poorer results, with most proving not to be searchable and only three yielding successful outcomes. Google and PubMed searches found some mutations and provided patchy information on phenotype. The results show that many web-based resources are not currently configured for fast and easy access to comprehensive mutation data, with only the isolated LSDBs providing optimal outcomes. Centralising this information within a common repository, coupled with a simple, all-inclusive interrogation process, would improve searching for all gene variation data.


Subject(s)
DNA/genetics , Databases, Genetic , Information Storage and Retrieval/methods , Internet , Mutation , Data Collection , Humans , Phenotype , PubMed
10.
Hum Mutat ; 32(5): 501-6, 2011 May.
Article in English | MEDLINE | ID: mdl-21305654

ABSTRACT

Genetic diseases are a pressing global health problem that requires comprehensive access to basic clinical and genetic data to counter. The creation of regional and international databases that can be easily accessed by clinicians and diagnostic labs will greatly improve our ability to accurately diagnose and treat patients with genetic disorders. The Human Variome Project is currently working in conjunction with human genetics societies to achieve this by establishing systems to collect every mutation reported by a diagnostic laboratory, clinic, or research laboratory in a country and store these within a national repository, or HVP Country Node. Nodes have already been initiated in Australia, Belgium, China, Egypt, Malaysia, and Kuwait. Each is examining how to systematically collect and share genetic, clinical, and biochemical information in a country-specific manner that is sensitive to local ethical and cultural issues. This article gathers cases of genetic data collection within countries and takes recommendations from the global community to develop a procedure for countries wishing to establish their own collection system as part of the Human Variome Project. We hope this may lead to standard practices to facilitate global collection of data and allow efficient use in clinical practice, research and therapy.


Subject(s)
Data Collection/methods , Databases, Genetic , Genetic Variation , Genome, Human/genetics , Humans , Internationality , Mutation , National Health Programs
11.
Hum Mutat ; 32(1): 2-9, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21089065

ABSTRACT

Developing countries have significantly contributed to the elucidation of the genetic basis of both common and rare disorders, providing an invaluable resource of cases due to large family sizes, consanguinity, and potential founder effects. Moreover, the recognized depth of genomic variation in indigenous African populations, reflecting the ancient origins of humanity on the African continent, and the effect of selection pressures on the genome, will be valuable in understanding the range of both pathological and nonpathological variations. The involvement of these populations in accurately documenting the extant genetic heterogeneity is more than essential. Developing nations are regarded as key contributors to the Human Variome Project (HVP; http://www.humanvariomeproject.org), a major effort to systematically collect mutations that contribute to or cause human disease and create a cyber infrastructure to tie databases together. However, biomedical research has not been the primary focus in these countries even though such activities are likely to produce economic and health benefits for all. Here, we propose several recommendations and guidelines to facilitate participation of developing countries in genetic variation data documentation, ensuring an accurate and comprehensive worldwide data collection. We also summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects.


Subject(s)
Data Collection/standards , Developing Countries , Genetic Variation/genetics , Humans
12.
Hum Mutat ; 32(4): 491-4, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21387463

ABSTRACT

The Human Variome Project (HVP) has established a pilot program with the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) to compile all inherited variation affecting colon cancer susceptibility genes. An HVP-InSiGHT Workshop was held on May 10, 2010, prior to the HVP Integration and Implementation Meeting at UNESCO in Paris, to review the progress of this pilot program. A wide range of topics were covered, including issues relating to genotype-phenotype data submission to the InSiGHT Colon Cancer Gene Variant Databases (chromium.liacs.nl/LOVD2/colon_cancer/home.php). The meeting also canvassed the recent exciting developments in models to evaluate the pathogenicity of unclassified variants using in silico data, tumor pathology information, and functional assays, and made further plans for the future progress and sustainability of the pilot program.


Subject(s)
Colonic Neoplasms/genetics , Genes, Neoplasm/genetics , Genetic Variation/genetics , Genome, Human , Databases, Genetic , Genetic Predisposition to Disease , Humans , Paris , United Nations
13.
Neurogenetics ; 12(3): 169-73, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21630033

ABSTRACT

The rate of DNA variation discovery has accelerated the need to collate, store and interpret the data in a standardised coherent way and is becoming a critical step in maximising the impact of discovery on the understanding and treatment of human disease. This particularly applies to the field of neurology as neurological function is impaired in many human disorders. Furthermore, the field of neurogenetics has been proven to show remarkably complex genotype-to-phenotype relationships. To facilitate the collection of DNA sequence variation pertaining to neurogenetic disorders, we have initiated the "Neurogenetics Consortium" under the umbrella of the Human Variome Project. The Consortium's founding group consisted of basic researchers, clinicians, informaticians and database creators. This report outlines the strategic aims established at the preliminary meetings of the Neurogenetics Consortium and calls for the involvement of the wider neurogenetic community in enabling the development of this important resource.


Subject(s)
Databases, Genetic/standards , Genetic Variation , Genetics, Medical/organization & administration , International Cooperation , Nervous System/metabolism , Algorithms , Congresses as Topic , Genetic Variation/physiology , Genetics, Medical/standards , Human Genome Project/organization & administration , Humans , Nervous System Diseases/genetics , Nervous System Diseases/metabolism , Research Report
15.
Hum Mutat ; 31(3): 366-7, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20052753

ABSTRACT

The May 2009 Human Variome Project (HVP) Forum "Towards Establishing Standards" was a round table discussion attended by delegates from groups representing international efforts aimed at standardizing several aspects of the HVP: mutation nomenclature, description and annotation, clinical ontology, means to better characterize unclassified variants (UVs), and methods to capture mutations from diagnostic laboratories for broader distribution to the medical genetics research community. Methods for researchers to receive credit for their effort at mutation detection were also discussed.


Subject(s)
Genome, Human , Polymorphism, Single Nucleotide , Algorithms , DNA Mutational Analysis , Databases, Genetic , Genetic Predisposition to Disease , Genetic Variation , Genomics/standards , Humans , Mutation , Phenotype , Sequence Analysis, DNA
16.
Hum Mutat ; 31(11): 1179-84, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20683926

ABSTRACT

More than 1,000 Web-based locus-specific variation databases (LSDBs) are listed on the Website of the Human Genetic Variation Society (HGVS). These individual efforts, which often relate phenotype to genotype, are a valuable source of information for clinicians, patients, and their families, as well as for basic research. The initiators of the Human Variome Project recently recognized that having access to some of the immense resources of unpublished information already present in diagnostic laboratories would provide critical data to help manage genetic disorders. However, there are significant ethical issues involved in sharing these data worldwide. An international working group presents second-generation guidelines addressing ethical issues relating to the curation of human LSDBs that provide information via a Web-based interface. It is intended that these should help current and future curators and may also inform the future decisions of ethics committees and legislators. These guidelines have been reviewed by the Ethics Committee of the Human Genome Organization (HUGO).


Subject(s)
Databases, Genetic/ethics , Genetic Variation , Confidentiality/ethics , Humans
17.
Hum Mutat ; 31(12): 1374-81, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20960468

ABSTRACT

The third Human Variome Project (HVP) Meeting "Integration and Implementation" was held under UNESCO Patronage in Paris, France, at the UNESCO Headquarters May 10-14, 2010. The major aims of the HVP are the collection, curation, and distribution of all human genetic variation affecting health. The HVP has drawn together disparate groups, by country, gene of interest, and expertise, who are working for the common good with the shared goal of pushing the boundaries of the human variome and collaborating to avoid unnecessary duplication. The meeting addressed the 12 key areas that form the current framework of HVP activities: Ethics; Nomenclature and Standards; Publication, Credit and Incentives; Data Collection from Clinics; Overall Data Integration and Access-Peripheral Systems/Software; Data Collection from Laboratories; Assessment of Pathogenicity; Country Specific Collection; Translation to Healthcare and Personalized Medicine; Data Transfer, Databasing, and Curation; Overall Data Integration and Access-Central Systems; and Funding Mechanisms and Sustainability. In addition, three societies that support the goals and the mission of HVP also held their own Workshops with the view to advance disease-specific variation data collection and utilization: the International Society for Gastrointestinal Hereditary Tumours, the Micronutrient Genomics Project, and the Neurogenetics Consortium.


Subject(s)
Genetic Variation/genetics , Genome, Human/genetics , Mutation/genetics , Data Collection , Databases, Genetic/economics , Humans , Motivation , Mutation/ethics , Paris , Precision Medicine , Software , Terminology as Topic , United Nations
18.
Hum Mutat ; 30(4): 493-5, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19306393

ABSTRACT

Several Locus-Specific DataBases (LSDBs) have recently been approached by larger, more general data repositories (including NCBI and UCSC) with the request to share the DNA variant data they have collected. Within the Human Genome Variation Society (HGVS) a document was generated summarizing the issues related to these requests. The document has been circulated in the HGVS/LSDB community and was discussed extensively. Here we summarize these discussions and present the concluded recommendations for LSDB data sharing with central repositories.


Subject(s)
Databases, Genetic , Genetic Variation , Genome, Human/genetics , Information Dissemination , Computational Biology/methods , Computational Biology/standards , Humans , Mutation , Polymorphism, Single Nucleotide
19.
Hum Mutat ; 30(4): 496-510, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19306394

ABSTRACT

The remarkable progress in characterizing the human genome sequence, exemplified by the Human Genome Project and the HapMap Consortium, has led to the perception that knowledge and the tools (e.g., microarrays) are sufficient for many if not most biomedical research efforts. A large amount of data from diverse studies proves this perception inaccurate at best, and at worst, an impediment for further efforts to characterize the variation in the human genome. Because variation in genotype and environment are the fundamental basis to understand phenotypic variability and heritability at the population level, identifying the range of human genetic variation is crucial to the development of personalized nutrition and medicine. The Human Variome Project (HVP; http://www.humanvariomeproject.org/) was proposed initially to systematically collect mutations that cause human disease and create a cyber infrastructure to link locus specific databases (LSDB). We report here the discussions and recommendations from the 2008 HVP planning meeting held in San Feliu de Guixols, Spain, in May 2008.


Subject(s)
Databases, Genetic , Genetic Variation , Genome, Human/genetics , Computational Biology/methods , Computational Biology/standards , Genetic Predisposition to Disease , Genotype , Humans , Information Dissemination , Mutation , Phenotype , Polymorphism, Genetic , Spain
20.
Genet Med ; 11(12): 843-9, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20010362

ABSTRACT

The collection of genetic variants that cause inherited disease (causative mutation) has occurred for decades albeit in an ad hoc way, for research and clinical purposes. More recently, the access to collections of mutations causing specific diseases has become essential for appropriate genetic health care. Because information has accumulated, it has become apparent that there are many gaps in our ability to correctly annotate all the changes that are being identified at ever increasing rates. The Human Variome Project (www.humanvariomeproject.org) was initiated to facilitate integrated and systematic collection and access to this data. This manuscript discusses how collection of such data may be facilitated through new software and strategies in the clinical genetics and diagnostic laboratory communities.


Subject(s)
Biomedical Research/methods , Databases, Genetic , Genetic Predisposition to Disease/genetics , Mutation , Genetic Variation , Genetics, Medical/methods , Genetics, Medical/organization & administration , Genetics, Medical/statistics & numerical data , Humans , International Cooperation
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