Review J Med Genet: first published as 10.1136/jmg.2007.052639 on 24 September 2007. Downloaded from General mutation databases: analysis and review R A George,1 T D Smith,2,3 S Callaghan,4 L Hardman,2 C Pierides,2,3 O Horaitis,2 M A Wouters,1 R G H Cotton2,3 c Additional tables are ABSTRACT mutations and indicating their source, general published online only at http:// Databases of mutations causing Mendelian disease play a databases list other properties of the mutation jmg.bmj.com/content/vol45/ crucial role in research, diagnostic and genetic health care and the patient concerned. Further, other features issue2 and can play a role in life and death decisions. These such as mutation maps and links, etc, may be databases are thus heavily used, but only gene or locus included. 1 Structural and Computational specific databases have been previously reviewed for In contrast to general mutation databases, Biology Program, Victor Chang Cardiac Research Institute, completeness, accuracy, currency and utility. We have databases of mutations in individual genes (Locus Darlinghurst, New South Wales, performed a review of the various general mutation Specific Databases, LSDBs) have been developed, Australia; 2 Genomic Disorders databases that derive their data from the published beginning with the globin mutations.10 These Research Centre, St Vincent’s literature and locus specific databases. Only two—the databases are a rich source of information on the Hospital Melbourne, Fitzroy, 3 Human Gene Mutation Database (HGMD) and Online gene itself and its mutations, and have been Victoria, Australia; Department 11–13 of Medicine, The University of Mendelian Inheritance in Man (OMIM)—had useful referred to as knowledge bases. A recent survey Melbourne, Melbourne, Victoria, numbers of mutations. Comparison of a number of indicated some 678 genes have databases14 that are Australia; 4 Victorian characteristics of these databases indicated substantial curated by experts in each gene. In a 2002 review Bioinformatics Consortium, inconsistencies between the two databases that included Claustres et al compared 80 data fields occurring Monash University, Melbourne, 15 Victoria, Australia absent genes and missing mutations. This situation over a sample of 100 representative databases. strengthens the case for gene specific curation of This review was based in part on earlier recom- Correspondence to: mutations and the need for an overall plan for collection, mendations of ideal database content which Dr Richard George, Structural curation, storage and release of mutation data. produced an entry form for submitting variants and Computational Biology Program, Victor Chang Cardiac to such a database (http://www.hgvs.org/entry. 12 13 Research Institute, 384 Victoria html). Street, Darlinghurst, NSW 2010, The collection of lists of mutations causing single Because of the need for a rapid and complete Australia; r.george@ access to mutation data we have reviewed a victorchang.edu.au gene disorders began when the definition of globin gene mutations at the protein level became number of GMDBs to assess their content, S Callaghan is deceased possible.1 It was then that Victor McKusick began currency and completeness. collecting a compendium of inherited syndromes Received 29 June 2007 Revised 5 September 2007 under the title Mendelian Inheritance in Man METHODS Accepted 9 September 2007 (MIM).2 After the advent of DNA sequencing, the Published Online First rate of discovery of mutations accelerated and Comparison of all GMDBs in relation to a number of http://jmg.bmj.com/ 24 September 2007 MIM began adding mutations to the compendium features as they were characterised. Around the same time, Seven GMDBs containing or providing access to David Cooper began specifically collecting genetic mutations were listed (table 1) and compared mutations to analyse their nature and frequency in according to the relevant criteria used by Claustres 15 order to find the most common sequence changes et al (see supplementary table 1, available online). in humans.3 Databases of this type are referred to Four other databases were included as controls or as general or central mutation databases (see Box 1 comparisons. These included the SNP databases: on September 24, 2021 by guest. Protected copyright. 16 17 18 for definitions) and today these two are available HGVbase and dbSNP; and two LSDBs: PAH online as Online Mendelian Inheritance in Man and Fanconi Anaemia. Characteristics were (OMIM)4–6 and the Human Gene Mutation assessed by one operator in October 2006. Database (HGMD),7 respectively. These and a number of newer general mutation databases Comparison of the main GMDBs containing reviewed in this study are summarised in table 1. mutations: OMIM and HGMD Although official usage statistics are not readily All genes and their variations listed in OMIM were accessible on the websites, the information stored taken from the omim.txt and mim2gene down- in these databases is extremely important and loadable files (ftp.ncbi.nih.gov; downloaded on 10 widely used. These databases are particularly October 2006). By text-mining the omim.txt file useful for those dealing in mutations found in we were able to group each variation into ‘‘inser- patients as the first questions asked are, ‘‘Is this tion’’; ‘‘deletion’’; ‘‘mutation’’ (including those sequence variation pathogenic?’’ and, ‘‘Has it been occurring in exons, introns and regulatory regions); found before?’’ If others have seen such a change and ‘‘other’’ categories. Programs written for text and have reported investigations showing it to be mining were developed in Perl5 and will be made pathogenic, this makes the work of the enquiring available upon request. laboratory or clinicians easier and more cost We compared the variations in the ‘‘mutation’’ effective. Among many other uses,9 those studying category extracted from OMIM to those in the This paper is freely available online under the BMJ Journals the function of genes and their products are using HGMD commercial release (version 6.3, 30 unlocked scheme, see http:// the experiments of nature to define essential base September 2006). Mutation data held in HGMD jmg.bmj.com/info/unlocked.dtl or amino acid changes. Besides defining the actual were collected by querying the Missense/nonsense, J Med Genet 2008;45:65–70. doi:10.1136/jmg.2007.052639 65 Review J Med Genet: first published as 10.1136/jmg.2007.052639 on 24 September 2007. Downloaded from 8 HGNC gene name, again using the NCBI files. For genes that Box 1: Definitions (Cotton and Scriver 1998) have not yet been allocated a HGNC name, the ENTREZ gene name was retained. c Mutation: Base changes shown to cause single gene, or Mendelian, disorders. This usage has been general in clinical Currency of data in HGMD in relation to mutations in the practice. literature c Polymorphism: Base changes having no clinical effect. This Issues of Human Mutation, starting with those that coincide usage has also been general in clinical practice. with the most recent HGMD public release, were reviewed to c Sequence variant: A recently preferred option for any base determine the currency of information in HGMD. Three change pathogenic at one extreme and with no effect at the different novel mutations reported in each issue (see supple- other. Its nature is specified as either causing or not causing mentary tables 1 and 2, available online) were randomly functional or pathological consequences. selected and then searched for in HGMD. This process was c Single nucleotide polymorphism (SNP): Initially coined to undertaken on three separate occasions for the public version of refer to single base changes of little or no functional HGMD: May 2004, May 2005 and January 2007. In January consequence, which were sought by researchers for use as 2007 the same mutations were also assessed in the commercial aids in gene mapping, common disease and release of HGMD (version 6.4, 15 December 2006). pharmacogenomic studies. The term certainly did not include mutations that cause single gene disorders. It appears that usage has strayed from that initial definition both from single Search for specific mutations in HOWDY, GeneCards, EBI, nucleotide changes to all sequence variants, and whether or Mutation Discovery and GDB not they cause single gene disorders. Two specific mutations were taken from the literature and c General mutation database (GMDB): Sometimes referred to searched for in the databases other than OMIM, HGMD and as central mutation databases, GMDBs strive to collect their LSDBs. These were a PAH mutation p.R158Q20 and PKD2 mutations in all genes and curate them centrally—for p.Q405X.21 The presence or absence of each mutation was example, HGMD and OMIM. recorded. c Locus specific database (LSDB): Databases of mutations, and relevant polymorphisms, in a single gene that are curated Number of mutations in GMDBs compared with the number in by an expert or experts in that gene. Sometimes the curator LSDBs may manage several genes they are researching or Four LSDBs of varying size were randomly selected and the diagnosing. number of mutations and polymorphisms found in each were c Conduit mutation database (CMDB): Displays mutations by recorded. These were then compared against mutation entries linking to LSDBs or GMDBs—for example, HOWDY. found in GMDBs, including the HGMD public release. RESULTS Splicing and Regulatory tables only in the HGMD database. Comparison of all GMDBs in relation to a number of features The nomenclature for many genes is often derived from Of the general databases checked against our 68 criteria (see http://jmg.bmj.com/ individual researchers, resulting in many aliases for a single supplementary table 1, available online) those that display gene. To ensure that we compared like with like, genes in both mutations are: GDB, HGMD, OMIM and Mutation Discovery OMIM and HGMD were converted to their Human Genome (although some polymorphisms are included as well in these Organisation (HUGO) Nomenclature Committee (HGNC) databases).