NCBI-101: Clinical Genetics, What does it mean? Malignant neoplasm ranked second as a cause of death in the United States in 1999 (Minino and Smith, 2001). A correlation between the malfunction of the breast cancer gene, BRCA1, and the occurrence of cancer has been established (Hall et al., 1992). Media and consumer health services quickly spread the word that our health lies in our genes. Diseases of the heart ranked first as a cause of death in the United States in 1999 (Minino and Smith, 2001). Is there a correlation of a gene malfunction and heart disease, too? Which genes are involved in a particular kind of cancer or heart disease? The genetic predisposition to complex diseases such as cancer or heart disease, where environmental factors influence health, becomes a valuable tool for predicting the possibility, not the guarantee of disease. The progress of the Human Genome Project over the last few years has lead to the development of many resources that compile information and unfold the links between biological data, such as gene mutations and diseases. The resources discussed below represent catalogs of genetic diseases as well as include tools to locate genes and view chromosome maps. With this article we focus on genetic information resources that receive federal funding, but many will provide links to valuable clinical information from resources not highlighted here. The resources are developed to empower the clinical geneticist as well as other professionals in the field of genetics research to make informed choices. An attempt is made to distinguish between general and specialized resources. However, the users should be familiar with Evaluating Internet Resources since publishing on the Web does not require a traditional review process as does publishing in professional journals. General Resources: OMIM GeneTestsGeneClinics GeneCards Spezialised Resources: CGAP Jablonski's MCA/MRS OrphaNet HuGENet Atlas of Genetics and Cytogenetics Molecular Databases: SKY/CGH dbSNP dbSTS References and Further Information Credits and Disclaimer General Resources OMIM (Online Mendelian Inheritance in Man) OMIM is a database of human genes and genetic disorders. The first compendium of Mendelian Inheritance in Man was published in 1966, when Dr. Victor A. McKusick and his colleagues at the Johns Hopkins University School of Medicine made the effort to catalog genetic traits. The online version of MIM (OMIM) became available in 1987 from Johns Hopkins and 1995 from the National Center of Biotechnolgy Information (NCBI). OMIM records include phenotypic descriptions and references for genetic disorders as well as molecular information such as allelic variations, mapping information and links to relevant molecular databases and maps. Cited references are linked to PubMed, but an exhaustive review of the literature would require a separate PubMed search. OMIM is still curated at the Johns Hopkins School of Medicine and updated daily. Since OMIM concentrates on inherited disorders, the database contains only little information on chromosomal aberrations. OMIM is open to the public but targeted to a professional audience as e.g., physicians, genetics researchers and students in science and medicine. Since OMIM is integrated in NCBI's ENTREZ retrival system, it is subject to text searching and complex boolean searching. Gene symbols as well as the full name of the gene can be entered. Also available are Entrez features such as Limits (limiting to clinical synopsis, allelic variants, chromosomal location, the mode of inheritance or to known cytogenetic map locations), Preview/Index, History, Clipboard and Details. GeneTestsGeneClinics GeneTestsGeneClinics is an initiative of University of Washington Children's Hospital Regional Center in Seattle, Washington, to provide centralized access to information for professionals in the field of clinical genetics. The contribution of information and service-information is voluntary and therefore not comprehensive. GeneTestsGeneClinics is free, but does require a one-time registration, and a User Name and Password to access the information. The information is provided under the following categories: Gene Reviews: Expert-authored, peer-reviewed, disease-specific reviews describe the application of genetic testing to the diagnosis, management, and genetic counseling of patients and families with hereditary disorders, and provide links to related resources and databases. Laboratory Directory: This directory lists US and international laboratories performing genetic testing by disease name. Clinic Directory: This directory lists US and international clinics providing genetic counseling and prenatal diagnosis by geographic location. Educational Materials: Educational materials include basic information on the use of genetic services, teaching materials for genetics professionals, and a glossary of terms used on this site. Questions such as: What is genetic testing?, Which different applications can genetic testing be used for?, What is a genetic consultation?, Who should have one and where can I get a consultation? Where and how do I order a genetic test? are being discussed. Summary Reports: Specific aggregate data on the availability and use of genetic testing are available following a formal request process. The sections Gene Reviews, the Laboratory and the Clinics Directory each have their own search interface, which is available from the homepage by clicking on the section name on the top bar of the page after the user log-on. The search options include searching by disease name disease feature gene name OMIM number or author. An advanced search option includes e.g., the choice between exact spelling and a phonetic search strings to circumvent misspelling. GeneCards GeneCards is an electronic encyclopedia of biological and medical information produced by the Crown Human Genomics Center and the Bioinformatics Unit of the Weizmann Institute of Science in Rehovot, Israel. The aim is to provide a user-friendly and easy-to-navigate access to information for human genes by making use of standardized gene nomenclature. The GeneCards database currently (April 2002) contains 72704 GeneCards (Genes). The data is extracted from many different sources and initiatives and is presented in a table with extensive link-outs for the ease of use. The table rows are organized as follows: Gene Synonyms References in other online gene-based resources Chromosomal location Proteins (including summaries on cell functions in regard to clinical aspects of diseases) Sequences SNPs (according to the NCBI SNP database) Similar genes in other organisms Disorders and mutations Medical News (including disease therapies and prognosis are given) Research articles in PubMed Additional sources of information, such as specialized databases, personal homepages and conferences GeneCards can be searched by keyword, gene symbol of alias or by using boolean operators. The exact word match is used when nothing else is specified (case doesn't matter). Keywords may be a human or mouse gene, protein, disease, cell type, tissue, chromosome or a related word. Gene symbol may be GenBank accession number, UniGene cluster ID or clone identifiers. Truncation can be used for a word family (develop*=development, developing, developed) or independently of word boundaries (e.g.,*synap*=synapse, presynaptic, postsynaptic, synaptophysin). Specialized Resources: CGAP (Cancer Genome Anatomy Project) In 1996 the National Cancer Institute (NCI) launched the Cancer Genome Anatomy Project (CGAP) as an interdisciplinary program to study the molecular differences between a normal cell and a cancer cell. Background information on the project can be viewed by following the Educational Resources link from the homepage, whereas the slide tour provides an overview of the CGAP concept. In brief, CGAP provides access to Genomic data for human and mouse, including expressed sequence tags (ESTs), gene expression patterns, single nucleotide polymorphisms (SNPs), cluster assemblies, and cytogenetic information. Informatics tools to query and analyze the data. Information on methods and resources for reagents developed by the project. An effort is made to categorize the information into: Genes: Information on specific genes and collections of genes. Chromosomes: Gene mapping, BAC clones, and Mitelman database of chromosome aberrations. Tissues: Information on CGAP and other cDNA libraries, gene expression, and SNPs. This section includes a Library Finder for the retrieval of cDNA libraries from dbEST and SAGE libraries. Pathways: Diagrams of biological pathways and protein complexes, with links to genetic resources for each known protein/enzyme. This section includes the BioCarta Pathways and the Kegg Pathways as well as related resources. Tools: Direct access to the analytic and data mining tools developed for the project. Methods: Method overviews and experimental protocols. Reagents: CGAP clone and library resources. Catalog of Resources: A catalog or inventory of all the CGAP resources for both human and mouse. However, resources within these categories are overlapping. The Gene Ontology Browser (GO Browser), for example, a tool to classify human and mouse genes by molecular function, biological process, and cellular component, can be found in the Genes as well as in the Tools section. The Chromosome section provides 4 maps to examine chromosomes: Mitelman's Database of Chromosome Aberrations in Cancer (updated quarterly), originally published by Mitelman and colleagues in Nature Genetics in 1997, can now be searched online by type of tumor, patient characteristics and/or cytogenetic characteristics to determine balances and unbalanced translocations. Depending on the information available and needed, different search options are supported: Quick Searcher Full Searcher The Mitelman Molecular Biology and Clinical (MBC) Associations Searcher (MBC Searcher) Recurrent Aberrations Reference Searcher CCAP FISH-mapped BACs (BAC clones mapped both cytogenetically by FISH and physically by STSs to the human genome) can be viewed by choosing a chromosome number (Cancer Chromosome Aberration Project). Genetic and Physical SNP Maps (genetic and physical locations of confirmed, validated, and predicted SNPs per individual chromosomes) can be viewed by choosing either the SNP or the Linkage map of one chromosome. NCBI's GeneMap99 (a physical map of >35,000 human gene-based markers, constructed by the International Radiation Hybrid Mapping Consortium) can also be viewed by choosing the chromosome number of the chromosome of interest. Jablonski's Multiple Congenital Anomaly/Mental Retardation (MCA/MRS) Syndromes The database is hosted at the National Library of Medicine and contains over 700 (of approximately 1600 - 2000) descriptions of congenital abnormalities associated with mental retardation including their clinical features. X-linked and chromosomal aberrations that have syndrome characteristics but are not routinely classified as syndromes in the literature can also be found. Despite looking up the alphabetic table of contents, the database can be searched by Keywords that can be limited to All Fields, or searched as Major Feature, Syndrome Name or Synonym, MeSH Term, OMIM Number or Personalia (to identify eponymous names of syndromes). Searching with boolean operators as well as searching with Medical Subject Headings (MESH) terms and Unified Medical Language System (UMLS) terms is supported. OrphaNet "OrphaNet is a relational database of rare diseases and orphan drugs for the general public. It aims to improve diagnosis, management and treatment of rare diseases. OrphaNet contains an on-line encyclopedia written by European experts and a list of services for patients and professionals. This list includes information about specialized outpatient clinics, diagnostic laboratories, current research projects and support groups." OphaNet currently contains information on 1,150 rare diseases that can be searched using a variety of search options (e.g. Disease, Signs, Outpatient clinics, Research programs, Clinical trials, Registry, Clinical test, Accreditation, Support group). The search options are made available under the categories "patients", "professionals", "support groups", "industry" and "public" to meet the users need. Most search options include the ability to type in own search requests or access an alphabetical listing or a thesaurus. OrphaNet is under development and will be available in multiple languages in the future. HuGENet The Human Genome Epidemiology Network (HuGENet), hosted on the Center of Disease Control and Prevention (CDC) website, aims to develop a network to exchange information on population-based human genome epidemiology. The database contains peer-reviewed literature on population-specific prevalence data on human gene variants, gene-environment interaction and more. HuGENet can be search by specifying a topic (gene name, health outcome, environmental factors), selecting a category (Association, Gene-environment Interaction, Gene-gene Interaction, Genetic Test, Prevalence of Gene Variants), selecting a publication date, and choosing the output format (Bibliographic Listing vs. Tabular Format). Atlas of Genetics and Cytogenetics in Oncology and Hematology The atlas is a collaborative project by GFCO, INFOBIOGEN and the University Hospital of Poitiers, France. The resource is a peer reviewed on-line journal and database containing information on genes involved in cancer, cytogenetics and clinical entities in cancer, and cancer-prone diseases. It is made and maintained by professionals in the field of cancer research and genomics and the contributions are reviewed before acceptance. The contents can be searched by chromosome number or by entering one of the following categories: Genes: Gene list Leukemia: Cytogenetic / Clinical Entities Solid Tumors Cancer-prone Diseases Deep Insight containing background information, study groups and case reports Portal: Sites and databases related to genetics, cytogenetics and oncology Teaching: Educational items in Human Genetics Molecular Databases: Spectral Karyotyping (SKY) and Comparative Genomic Hybridization (CGH) "Spectral Karyotyping (SKY) and Comparative Genomic Hybridization (CGH) are complementary fluorescent molecular cytogenetic techniques. SKY permits the simultaneous visualization of all human or mouse chromosomes in a different color, facilitating the identification of chromosomal aberrations. CGH utilizes the hybridization of differentially labeled tumor and reference DNA to generate a map of DNA copy number changes in tumor genomes." The database can be searched by entering a single topic, or any combination of topics in any order into the textbox and clicking "GO". Searchable Topics are Submitter (by last name), Case name, Cell line, Chromosome (arm or breakpoint), Diagnosis (morphology), using ICD-0-3, Site of disease (topography), using ICD-0-3, Specific types of treatment (e.g., drugs), Specific hereditary disorder, Mouse strain and genotype and Media type and media selection features. Special features of the page are: Metaphrase, a Metathesaurus Browser containing different biomedical vocabularies, including ICD-0-3, the International Classification of Diseases for Oncology (ICD). Database of Single Nucleotide Polymorphisms (dbSNP) Single nucleotide polymorphisms (SNPs) are the most common variations within populations. In order to facilitate genetics studies the National Human Genome Research Institute (NHGRI) in collaboration with the National Center for Biotechnology Information (NCBI) launched dbSNP, which currently contains over 4.100.000 submissions of SNPs (April 2002) of both single base nucleotide substitutions and short deletion and insertion polymorphism. The database can be searched for genetic variations by using Unique Identifiers the Free Form and appropriate search tags the Easy Form Batch Query Locus IDs such as, Gene Name or Symbol, Gene Product, Accession Number or Gene Ontology Information (Biological Process, Cellular Location, Molecular Function) Submission Information such as Submitter, Batch, Method, Population description or the geographic classification of a population, Publication details or by the Chromosome reports Markers by entering two STS markers that are mapped on the same chromosome BLAST to compare your sequence against the SNP BLAST database of human. Database of "Sequence Tagged Sites" (dbSTS) "dbSTS is an NCBI resource that contains sequence and mapping data on short genomic landmark sequences or Sequence Tagged Sites." STS division entries in GenBank can be retrieved using Entrez and STS nucleotide sequences can be searched using BLAST. UniSTS is a NCBI resource that reports information about markers, or Sequence Tagged Sites (STS). Electronic PCR can be used to test a DNA sequence for the presence of sequence tagged sites (STSs). Further Information: Databases: The Genome Database (Site Map) Human Genome Variation Society including Variation Databases and Related Sites Human Gene Mutation Database including Locus-Specific Mutation databases Tumor Gene Database Specialized Database can also be listed and found in the "Database Issues" of the journal Nucleic Acid Research in the database categories e.g., Comparative Genomics, Gene Expression, Genetic and Physical Maps, Genomic Databases, Intermolecular Interactions, Metabolic Pathways and Cellular Regulation, Mutation Databases or Pathology. Gateways and Newsletters: NCBI's Guide to Human Genome Resources UK Human Genome Mapping Project Resource Center National Human Genome Research Institute (NHGRI) National Cancer Institute Huntsman Cancer Institute, Salt Lake City, Utah Human Genome Landmarks (a poster) Eccles Institute of Human Genetics, University of Utah Health Sciences Center, University of Utah Nature's Genome Gateway including a link list for Genome Related Sites BioMedNet Reviews (Genetics)(Genomics)(CancerBiology) Human Genome most used links Consumer Health Information (Eccles Library) GeneLetter published by GeneSage Information on the Human Genome Project and Educational Pages: DOE's Human Genome Project Information Dolan DNA Learnig Center including "DNA from the Beginning" The Human Genome Project: "Exploring Our Molecular Selves" from the National Human Genome Research Institute (NHGRI) The Human Genome from the Wellcome Trust Foundation, UK Ethics and Genetics: Bioethics Resources on the Web References and Readings: Guttmacher AE. (2001) Human Genetics on the Web. Annu. Rev. Genomics Hum. Genet. 2:213-233. Stewart A, Haites N, Rose P (2001) Online medical genetics resources: a UK perspective. British Medical Journal 322 (7293):1037-1040 Minino AM and Smith BL (2001) Deaths: Leading Causes for 1999. National Vital Statistics Reports 49 (11): 2001-1120. Hall JM, Friedman L, Guenther C, Lee MK, Weber JL, Black DM, King MC. (1992) Closing in on a breast cancer gene on chromosome 17q. Am J Hum Genet 50:1235-42. McKusick VA. (1966) Mendelian inheritance in man; catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes. Baltimore, Johns Hopkins Press Mitelman F, Mertens F, Johansson B. (1997) A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat Genet Apr;15 Spec No:417-74 (Comments: Nat Genet. 1997 Apr;15 Spec No:413 and Nat Genet. 1997 Apr;15 Spec No:415-6.) Credits This material was adapted from NCBI's Educational Collaboration with course modules developed by Janet Ohles (Medical Sciences Library, New York Medical College), Kris Alpi (Weill Cornell Medical Library, New York), Michele R. Tennant, Ph.D. (Health Science Center Libraries, University of Florida), Jennifer Lyon (Eskind Biomedical Library, Vanderbilt University Medical Center) and others. Disclaimer These databases are ment to compile and disseminate information. They are in no way substitute for a visit to the health care provider.