PMC:1852721 / 2129-12146 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/1852721","sourcedb":"PMC","sourceid":"1852721","source_url":"https://www.ncbi.nlm.nih.gov/pmc/1852721","text":"Origins and Evolution of the Structure and Organization and Content of MIM/OMIM\nMIM had its origins in three different endeavors3: first, the annual reviews of medical genetics that my colleagues and I in the Moore Clinic at Johns Hopkins prepared for each of 6 years, 1958–19634, 5; second, a catalog of X-linked traits that I compiled in 1962 as an assessment of the genetic content of the X chromosome6, 7; and, third, a catalog of autosomal recessive phenotypes that I prepared in 1963 as a resource for identifying both “old” and “new” recessive diseases in studies of the Old Order Amish.8, 9\nIn the original three catalogs corresponding to the three major modes of Mendelian inheritance, the entries were arranged alphabetically according to the preferred title of the particular phenotype, and numbering was done consecutively. By the 11th book edition in 1994,2 the X-linked catalog had been joined by two other chromosome-specific catalogs: those for the Y chromosome and for the mitochondrial chromosome. Entries in the original autosomal dominant, autosomal recessive, and X-linked catalogs had been assigned unique identification numbers, beginning with 1, 2, and 3, respectively. Entries in the two new chromosome-specific catalogs were given unique numbers beginning with 4 (Y-linked) and 5 (mitochondrial). (Entries were given 4-digit numbers in the first [1966] and second [1968] book editions of MIM. Entry numbers were expanded to 5 digits with the third [1975] edition by adding a zero to the 4-digit numbers of previously existing entries and to 6 digits in the 9th [1990] edition by the same method.)\nSince May 1994, a distinction between autosomal dominant and autosomal recessive traits has not been maintained in MIM. All autosomal traits (or genes) for which new entries were created were added consecutively to a new catalog, with 6-digit numbers beginning with 6. No new entries were added to the original autosomal dominant and autosomal recessive catalogs that had unique entry numbers beginning with 1 and 2, although copious new information bearing on previously existing entries in these original catalogs has been added. (A caveat: some entries that remain in the catalogs with numbers beginning with 1 or 2 relate to phenotypes not now considered dominant or recessive, respectively, in the light of newer understanding.)\nThe reasons for discontinuing the distinction between autosomal dominant and autosomal recessive entries included the fact that entries were being created for an increasing number of genes for which there was extensive information, including location on a specific autosome, but no associated Mendelian phenotypic variation with either dominant or recessive inheritance. Also, the distinction is only relative—that is, whether dominant or recessive sometimes depends on the level at which the phenotype is analyzed. For example, in several of the red-cell enzymopathies, the deficiency state is autosomal recessive but the electrophoretic variation is likely to be demonstrable in the heterozygote—that is, it is dominant, or at least intermediate, in its inheritance. Furthermore, there are rather numerous examples of particular phenotypes that are inherited as dominant or recessive based on different mutations in the same gene. Table 15 on page l in the preface of MIM122 listed 11 disorders that have both dominant and recessive forms resulting from different mutations in the same gene. Some mutations that cause absent function of the protein—that is, null mutations—produce phenotypic effects only with homozygosity; missense mutations may cause the disorder because of a dominant negative effect when, for example, the structure of a protein that is part of a heteromeric protein complex is altered.\nStarting with the first edition of MIM, two classes of entries were differentiated. Those for which the particular mode of inheritance was considered quite certain and the phenotype was thought to be distinct from any already represented by an entry were distinguished by an asterisk (*) preceding the unique entry number. The asterisk was omitted in the case of entries for which the phenotype was less certainly Mendelian, less clearly of the particular mode of inheritance, or not distinct from a phenotype described in another entry. The inclusion of these unasterisked entries was considered important for heuristic purposes.\nFrom the beginning, the gene behind the phenotype was always kept in mind. For most of the first 15 years of the catalogs and more, however, there was little way to know whether a given phenotype was in fact caused by mutation in a single gene or might be caused by mutation in any one of two or more different genes, and it was usually impossible to tell whether two or more quite different phenotypes were due to mutations in the same gene. Since 1990, separate entries have been, as a rule, created for phenotypes and the genes that have mutations causing those phenotypes.\nThe practice of separate entries for genes and phenotypes was initiated, in large part, to handle the issues of one phenotype–several genes and of one gene–several phenotypes. Entries describing phenotypes for which the mutational basis has been found in one or more genes are flagged with a number sign (#) preceding the unique entry number, and the initial paragraph indicates the entry number of the gene(s) in which the mutation(s) is described. Gene entries have an asterisk preceding the unique number. Entries that contain both phenotype and gene information are flagged with a plus sign (+); X-linked examples include HPRT (MIM +308000), G6PD (MIM +305900), and HEMA (MIM +306700). Beginning in 2004, other Mendelizing phenotypes, regardless of whether they have been mapped, have been denoted by a percent sign (%) preceding the entry number when the causative gene has not yet been identified and cloned. Table 1 presents current statistics on these several categories of entries.\nTable 1 OMIM Statistics as of January 29, 2007\nNo. of Entries by Category\nEntry Classification Autosomal X Linked Y Linked Mitochondrial Total\n* Gene with known sequence 10,644 495 48 37 11,224\n+ Gene with known sequence and phenotype 356 32 0 0 388\n# Phenotype description, molecular basis known 1,851 169 2 26 2,048\n% Mendelian phenotype or locus, molecular basis unknown 1,411 134 4 0 1,550\nOther, mainly phenotypes with suspected Mendelian basis 2,014 144 2 0 2,160\n Total 16,276 974 56 63 17,370\nBeginning with hemoglobinopathies as early as the first edition (1966) and in full force by 1988 (MIM8), allelic variants (AVs) (or mutations) have been appended to the gene entries—for example, the beta-globin gene (HBB) entry (MIM +141900). At present, each AV is given a unique 10-digit number, consisting of the primary 6-digit number for the gene followed by a 4-digit extension beginning with .0001 for the first listed AV. As of December 4, 2006, the HBB entry cataloged 537 AVs of the HBB gene, numbered MIM +141900.0001 to +141900.0537. The entry of each AV consists of the title of the trait (phenotype) determined by the mutation, the gene symbol and the shorthand description of the mutation,10, 11, 12 text providing a varying amount of information on the family(ies) or population(s) studied, the details of the specific DNA change, and peculiarities of phenotype and genetics. “Allelic Variants” was selected as the heading of that section of gene entries rather than “Mutations” because, together, they represent an allelic series. Furthermore, the title of each AV is the phenotype (not the mutation), which, in some instances, can be an electrophoretic or antigenic polymorphism of an enzyme or plasma protein. The molecular bases of the variation in blood-group antigens are given as AVs, for example.\nSelection of particular mutations of a given gene for inclusion as AVs in OMIM has been based on general criteria, including the following: (1) the first or first few disease-related mutations to be identified in the given gene; (2) any mutation with a particularly high frequency, such as Phe508del in the CFTR gene (MIM *602421.0001) in cystic fibrosis (MIM #219700); (3) a mutation related to a distinct phenotype not previously represented in the list; (4) mutations of historical interest, such as the specific mutation in the family or population in which the phenotype was first described—for example, the mutation in the CLCN1 gene (MIM *118425.0006) in the family of Dr. Thomsen, who first described Thomsen disease (MIM #160800); (5) any mutation with a peculiar ethnic or geographic distribution; (6) any mutation arising through a distinctive mutagenic mechanism such as gene conversion (as in classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency [MIM *201910.0001]) or gene fusion (as in Hb Lepore [MIM +142000.0019ff]); (7) any mutation producing the phenotype through a distinctive pathogenetic mechanism; (8) mutations associated with autosomal dominant versus autosomal recessive inheritance with different mutations in the same gene, as in therecessive (MIM *139250.0005) and dominant (MIM *139250.0007) forms of isolated growth hormone deficiency due to allelic mutations in the growth hormone gene (GH1); and (9) polymorphisms demonstrating association with disease—for example, the Y402H polymorphism of complement factor H (CFH [MIM *134370.0008]) in age-related macular degeneration (MIM #603075). The last category represents so-called susceptibility genes, as discussed later. Most are part of the multifactorial basis of common disorders.\nOMIM provides links to comprehensive mutation listings, including the Human Gene Mutation Database curated at Cardiff, and many locus-specific mutation databases (LSDBs)—for example, PAHdb (Phenylalanine Hydroxylase Locus Knowledgebase) and CFTRdb (Cystic Fibrosis Mutation Database) for PKU and cystic fibrosis mutations, respectively, as well as the Human Genome Variation Society based in Melbourne, which maintains information on \u003e500 LSDBs.","divisions":[{"label":"title","span":{"begin":0,"end":79}},{"label":"p","span":{"begin":80,"end":598}},{"label":"p","span":{"begin":599,"end":1622}},{"label":"p","span":{"begin":1623,"end":2356}},{"label":"p","span":{"begin":2357,"end":3766}},{"label":"p","span":{"begin":3767,"end":4397}},{"label":"p","span":{"begin":4398,"end":4974}},{"label":"p","span":{"begin":4975,"end":6466}},{"label":"table-wrap","span":{"begin":5966,"end":6466}},{"label":"label","span":{"begin":5966,"end":5973}},{"label":"caption","span":{"begin":5974,"end":6012}},{"label":"p","span":{"begin":5974,"end":6012}},{"label":"table","span":{"begin":6013,"end":6466}},{"label":"tr","span":{"begin":6013,"end":6039}},{"label":"th","span":{"begin":6013,"end":6039}},{"label":"tr","span":{"begin":6040,"end":6108}},{"label":"th","span":{"begin":6040,"end":6060}},{"label":"th","span":{"begin":6061,"end":6070}},{"label":"th","span":{"begin":6071,"end":6079}},{"label":"th","span":{"begin":6080,"end":6088}},{"label":"th","span":{"begin":6089,"end":6102}},{"label":"th","span":{"begin":6103,"end":6108}},{"label":"tr","span":{"begin":6109,"end":6159}},{"label":"td","span":{"begin":6109,"end":6135}},{"label":"td","span":{"begin":6136,"end":6142}},{"label":"td","span":{"begin":6143,"end":6146}},{"label":"td","span":{"begin":6147,"end":6149}},{"label":"td","span":{"begin":6150,"end":6152}},{"label":"td","span":{"begin":6153,"end":6159}},{"label":"tr","span":{"begin":6160,"end":6215}},{"label":"td","span":{"begin":6160,"end":6200}},{"label":"td","span":{"begin":6201,"end":6204}},{"label":"td","span":{"begin":6205,"end":6207}},{"label":"td","span":{"begin":6208,"end":6209}},{"label":"td","span":{"begin":6210,"end":6211}},{"label":"td","span":{"begin":6212,"end":6215}},{"label":"tr","span":{"begin":6216,"end":6283}},{"label":"td","span":{"begin":6216,"end":6262}},{"label":"td","span":{"begin":6263,"end":6268}},{"label":"td","span":{"begin":6269,"end":6272}},{"label":"td","span":{"begin":6273,"end":6274}},{"label":"td","span":{"begin":6275,"end":6277}},{"label":"td","span":{"begin":6278,"end":6283}},{"label":"tr","span":{"begin":6284,"end":6359}},{"label":"td","span":{"begin":6284,"end":6339}},{"label":"td","span":{"begin":6340,"end":6345}},{"label":"td","span":{"begin":6346,"end":6349}},{"label":"td","span":{"begin":6350,"end":6351}},{"label":"td","span":{"begin":6352,"end":6353}},{"label":"td","span":{"begin":6354,"end":6359}},{"label":"tr","span":{"begin":6360,"end":6435}},{"label":"td","span":{"begin":6360,"end":6415}},{"label":"td","span":{"begin":6416,"end":6421}},{"label":"td","span":{"begin":6422,"end":6425}},{"label":"td","span":{"begin":6426,"end":6427}},{"label":"td","span":{"begin":6428,"end":6429}},{"label":"td","span":{"begin":6430,"end":6435}},{"label":"tr","span":{"begin":6436,"end":6466}},{"label":"td","span":{"begin":6436,"end":6442}},{"label":"td","span":{"begin":6443,"end":6449}},{"label":"td","span":{"begin":6450,"end":6453}},{"label":"td","span":{"begin":6454,"end":6456}},{"label":"td","span":{"begin":6457,"end":6459}},{"label":"td","span":{"begin":6460,"end":6466}},{"label":"p","span":{"begin":6467,"end":7787}},{"label":"p","span":{"begin":7788,"end":9571}}],"tracks":[{"project":"2_test","denotations":[{"id":"17357067-16824022-2054032","span":{"begin":128,"end":129},"obj":"16824022"},{"id":"17357067-13932119-2054033","span":{"begin":404,"end":405},"obj":"13932119"},{"id":"17357067-14209042-2054034","span":{"begin":594,"end":595},"obj":"14209042"},{"id":"17357067-14280821-2054035","span":{"begin":597,"end":598},"obj":"14280821"},{"id":"17357067-9450896-2054036","span":{"begin":7171,"end":7173},"obj":"9450896"},{"id":"17357067-10612815-2054036","span":{"begin":7171,"end":7173},"obj":"10612815"}],"attributes":[{"subj":"17357067-16824022-2054032","pred":"source","obj":"2_test"},{"subj":"17357067-13932119-2054033","pred":"source","obj":"2_test"},{"subj":"17357067-14209042-2054034","pred":"source","obj":"2_test"},{"subj":"17357067-14280821-2054035","pred":"source","obj":"2_test"},{"subj":"17357067-9450896-2054036","pred":"source","obj":"2_test"},{"subj":"17357067-10612815-2054036","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#9993ec","default":true}]}]}}