Mendelian Inheritance in Man and Its Online Version, OMIM
2007; Elsevier BV; Volume: 80; Issue: 4 Linguagem: Inglês
10.1086/514346
ISSN1537-6605
Autores Tópico(s)Genomic variations and chromosomal abnormalities
ResumoLast year marked the 40th anniversary of the publication of the first print edition of Mendelian Inheritance in Man (MIM).1McKusick VA. Mendelian inheritance in man: catalogs of autosomal dominant, autosomal recessive and X-linked phenotypes (1966, 1st ed; 1969, 2nd ed; 1971, 3rd ed; 1975, 4th ed; 1978, 5th ed; 1983, 6th ed; 1986, 7th ed; 1988, 8th ed; 1990, 9th ed; 1992, 10th ed). Johns Hopkins University Press, Baltimore.Google Scholar This seems an appropriate juncture at which to review its origins, evolution, and present status, including and particularly those of its online version, OMIM (Online Mendelian Inheritance in Man). This is an opportunity, at the same time, to review in brief the rapid progress in an important part of medical genetics and genomics, as chronicled in MIM/OMIM over these 40 years, and to contemplate the future challenges of OMIM. MIM1McKusick VA. Mendelian inheritance in man: catalogs of autosomal dominant, autosomal recessive and X-linked phenotypes (1966, 1st ed; 1969, 2nd ed; 1971, 3rd ed; 1975, 4th ed; 1978, 5th ed; 1983, 6th ed; 1986, 7th ed; 1988, 8th ed; 1990, 9th ed; 1992, 10th ed). Johns Hopkins University Press, Baltimore.Google Scholar, 2McKusick VA. Mendelian inheritance in man: a catalog of human genes and genetic disorders (1994, 11th ed; 1998, 12th ed). Johns Hopkins University Press, Baltimore.Google Scholar is a comprehensive knowledgebase of human genes and genetic disorders. It consists of full-text overviews of genes and genetic phenotypes, particularly disorders, and is useful to students, researchers, and clinicians. It was initiated in the early 1960s as a trilogy of catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes. It has been maintained as an electronic file since 1964 and has been published in 12 print editions (fig. 1), the first in 1966, the most recent (in three volumes) in 1998. (Various editions of MIM were translated into Russian [1976], Spanish [1976], and Mandarin [1996]; see fig. 2.) In 1987, it became generally available on the Internet, under the designation "OMIM," from the Welch Medical Library at Johns Hopkins University. Since December 1995, it has been distributed on the World Wide Web from the National Center for Biotechnology Information (NCBI) of the National Library of Medicine. This knowledgebase is updated daily. Authoring and editing are headquartered at Johns Hopkins University School of Medicine.Figure 2Foreign-language editions of MIM: (left to right) Spanish (Mexican) edition, translated by Rudolfo Guzmán Toledano, 1976; Russian edition, translated by E. K. Gentera and V. I. Ivanova, 1976; and Mandarin edition, translated by Wilson H. Y. Lo and others (two volumes), 1996.View Large Image Figure ViewerDownload Hi-res image Download (PPT) MIM had its origins in three different endeavors3McKusick VA A 60-year tale of spots, maps, and genes.Annu Rev Genomics Hum Genet. 2006; 7: 1-27Crossref PubMed Scopus (37) Google Scholar: 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, 1958–19634McKusick VA and contributors Medical Genetics 1958-1960: an annotated review. Mosby, St. Louis1961Google Scholar, 5McKusick VA and contributors Medical genetics 1961-1963: an annotated review. Pergamon Press, Oxford, United Kingdom1965Google Scholar; second, a catalog of X-linked traits that I compiled in 1962 as an assessment of the genetic content of the X chromosome6McKusick VA On the X chromosome of man.Quart Rev Biol. 1962; 37: 69-175Crossref PubMed Scopus (37) Google Scholar, 7McKusick VA On the X chromosome of man. American Institute of Biological Sciences, Washington, DC1964Google Scholar; 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.8McKusick VA Hostetler JA Egeland JA Genetic studies of the Amish: background and potentialities.Bull Johns Hopkins Hosp. 1964; 115: 203-222PubMed Google Scholar, 9McKusick VA Hostetler JA Egeland JA Eldridge R The distribution of certain genes in the Old Order Amish.Cold Spring Harb Symp Quant Biol. 1964; 29: 99-113Crossref PubMed Scopus (35) Google Scholar In 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 1994,2McKusick VA. Mendelian inheritance in man: a catalog of human genes and genetic disorders (1994, 11th ed; 1998, 12th ed). Johns Hopkins University Press, Baltimore.Google Scholar 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.) Since 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.) The 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 MIM122McKusick VA. Mendelian inheritance in man: a catalog of human genes and genetic disorders (1994, 11th ed; 1998, 12th ed). Johns Hopkins University Press, Baltimore.Google Scholar 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. Starting 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. From 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. The 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.Table 1OMIM Statistics as of January 29, 2007No. of Entries by CategoryEntry ClassificationAutosomalX LinkedY LinkedMitochondrialTotal* Gene with known sequence10,644495483711,224+ Gene with known sequence and phenotype3563200388# Phenotype description, molecular basis known1,8511692262,048% Mendelian phenotype or locus, molecular basis unknown1,411134401,550Other, mainly phenotypes with suspected Mendelian basis2,014144202,160 Total16,276974566317,370 Open table in a new tab Beginning 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,10Antonarakis SE Nomenclature Working Group Recommendations for a nomenclature system for human gene mutations.Hum Mutat. 1998; 11: 1-3Crossref PubMed Scopus (853) Google Scholar, 11Den Dunnen JT Antonarakis SE Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.Hum Mutat. 2000; 15: 7-12Crossref PubMed Scopus (1539) Google Scholar, 12Den Dunnen JT Antonarakis SE Nomenclature for the description of human sequence variations.Hum Genet. 2001; 109: 121-124Crossref PubMed Scopus (822) Google Scholar 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. Selection 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. OMIM 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 >500 LSDBs. The first print edition of MIM in 1966 had the subtitle Catalogs of Autosomal Dominant, Autosomal Recessive and X-linked Phenotypes.1McKusick VA. Mendelian inheritance in man: catalogs of autosomal dominant, autosomal recessive and X-linked phenotypes (1966, 1st ed; 1969, 2nd ed; 1971, 3rd ed; 1975, 4th ed; 1978, 5th ed; 1983, 6th ed; 1986, 7th ed; 1988, 8th ed; 1990, 9th ed; 1992, 10th ed). Johns Hopkins University Press, Baltimore.Google Scholar In the 1994 edition,2McKusick VA. Mendelian inheritance in man: a catalog of human genes and genetic disorders (1994, 11th ed; 1998, 12th ed). Johns Hopkins University Press, Baltimore.Google Scholar the subtitle became A Catalog of Human Genes and Genetic Disorders—a reflection of the progress in the field since the 1960s. Nearly all of the 1,486 entries in the first edition of MIM discussed phenotypes. As of January 29, 2007, 6,146 of the >17,300 entries in OMIM represented phenotypes (see table 1 and fig. 3); the rest related to genes. Beginning in the late 1960s, entries were created in MIM for individual genes for which no associated Mendelian phenotype was known. The method of interspecific (e.g., mouse-human) somatic cell hybridization made it possible to map genes to specific human chromosomes without the existence of a Mendelizing phenotype that could be used in family linkage studies. The difference between the genomes of the two species in the hybrid substituted for the differences between the genomes inherited from father and mother used in family linkage mapping. Thus, when the thymidine kinase gene (TK1 [MIM *188300]) was mapped to chromosome 17 by study of mouse-human hybrid cell lines,13Migeon B Miller CS Human-mouse somatic cell hybrids with single human chromosome (group E): link with thymidine kinase activity.Science. 1968; 162: 1005-1006Crossref PubMed Scopus (67) Google Scholar, 14Miller OJ Allderdice PW Miller DA Human thymidine kinase gene locus: assignment to chromosome 17 in a hybrid of man and mouse cells.Science. 1971; 173: 244-245Crossref PubMed Scopus (78) Google Scholar an entry was created for the gene, even though no Mendelian variation was known. Already, separate entries had been created for hemoglobin genes such as HBB, the lactate dehydrogenase genes such as LDHA (MIM +150000), and the G6PD gene (MIM +305900), among others. As mapping and cloning of genes advanced, the genes involved were given new entries in MIM, again although no Mendelian variation may have been known. Until the generic autosomal catalog was established (in 1994), autosomal "gene entries" were arbitrarily incorporated in the autosomal dominant catalog. In the accessioning and curating of gene entries, OMIM works closely with the NCBI reference sequence project and the Human Genome Organisation (HUGO) nomenclature committee. Because each group is involved in curating genes and sequence information, a method for sharing each group's analyses was established under the direction of Donna Maglott at NCBI. This collaborative effort resulted in the public resource "Locus Link" and its successor "Entrez Gene." This initiative allows Alan Scott, OMIM's Deputy Scientific Director for Genes, to review genes in OMIM, to remove duplicates, and to identify "new" genes for consideration of inclusion in OMIM. This is a considerable undertaking, since nearly 23,000 genes with supporting sequence have been identified. MIM has been maintained on computer since early 1964.15Hamosh A Scott AF Amberger JS Bocchini CA McKusick VA Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders.Nucleic Acids Res. 2005; 33: D514-D517Crossref PubMed Scopus (2192) Google Scholar In those pre–word processor days, maintenance on the mainframe computer was a boon to the updating process and facilitated preparation of camera copy, including author and subject indices, for book publication. That advantage for book publication continued. For example, from 1986 (MIM7) to 1994 (MIM11), it was possible to produce a print edition in 4 months at 2-year intervals. With closing of the files on March 1, bound books would be available by July 1. A time-consuming task during those 4 months was preparation of the front material (including the Synopsis of the Human Gene Map) and the indices. The process of vetting the indices in preparation for the book was valuable for detection of errors, including duplications, misspellings, inconsistent nomenclature, etc. The book was published by photo-offset of the computer printout (in all uppercase letters for the first three editions, 1966, 1968, and 1971) and of camera-ready copy prepared by automatic typesetting in the subsequent editions. In the 1980s, a new era began, with the adoption of MIM by the National Library of Medicine as the test bed for the development of IRx (Information Retrieval Experiment), a method of authoring and editing that permitted the rapid search of specific text material.16Harman D, Benson D, Fitzpatrick L, Huntzinger R, Goldstein C (1988) IRx: an information retrieval system for experimentation and user applications. Proceedings of RIAO 88 Conference "User-Oriented Content-Base Text and Image Handling," Cambridge, MA, March 21–24Google Scholar An online version of the 6th edition of MIM (1983) with updates and with the IRx search engine was demonstrated at the Bar Harbor Medical Genetics Course in July 1985 and was used as a resource at the eighth Human Gene Mapping Workshop in Helsinki in August 1985. By the fall of 1985, an online version of MIM, now called "OMIM," with the IRx search engine became a major aid in authoring and editing OMIM. Searchability helped to avoid duplications and inconsistencies and allowed entries to be related to each other—cross-referenced—more easily. Beginning in September 1987, OMIM was made generally accessible on the Internet from the Welch Medical Library of Johns Hopkins University. The informatics aspects of OMIM were transferred to the NCBI of the National Library of Medicine on December 1, 1995. Thus, in the 31 years from 1964 to 1995, MIM went from a solitary resource on magnetic tape to a cornerstone genetics resource on the World Wide Web, integrated with other primary genetic data sources. OMIM was one of the first electronic resources to exploit the advantages of the Web. Nosology (literally meaning "the study of disease" but customarily taken to mean the classification or delineation of disease), nosography ("the description of disease"), and the nomenclature of disease have necessarily been central considerations throughout the history of MIM. Indeed, nosology and nosography, viewed as the delineation of distinct genetic traits, are the main bases for assembling MIM. The basic premise has been that "Mendelization" indicates that the phenotype represents a distinct disorder or trait related to a specific mutation in a specific gene and deserves a specific name. In his monograph entitled Nosography,17Faber KH Nosography. 2nd ed. Paul B Hoeber, New York1930Google Scholar which was published in 1930, Knut Faber, Copenhagen professor of medicine, attributed to Mendel a major, albeit indirect, role in guiding thinking along lines of specific disease entities with specific etiology (causation), comparable to the role played by the pioneers in bacteriology in the late 1800s and early 1900s. Two hundred years ago, angina pectoris, asthma, consumption, dropsy, jaundice, stroke, and many symptom complexes were viewed and managed as though they were distinct entities with a single etiology. Nosology and the related naming of genetic disorders have both practical and theoretical significance—practical because of their importance to diagnosis, prognosis, and management and theoretical because of the implication that the disorder represents a distinct entity with a distinct mutational basis. These were important topics of discussion at the five annual conferences on the clinical delineation of birth defects held at the Johns Hopkins Hospital (1968–1972). (The proceedings of these five conferences on the Clinical Delineation of Birth Defects were published by the March of Dimes in 16 volumes. See, for example, the publication on skeletal dysplasias, which were discussed on the 3rd and 4th days of the first conference in 1968.18Birth Defects Orig Art Ser. 1969; 5: 1-396Google Scholar) When a Mendelizing disorder was described in a single large kindred or in a collection of kindreds, the question arose as to whether the condition was the same as a previously described entity or the same in all kindreds studied. The question brought out debates between "lumpers" and "splitters."19McKusick VA Lumpers and splitters, or the nosology of genetic disease.Birth Defects Orig Art Ser. 1969; 5: 23-32Google Scholar, 20McKusick VA Lumpers and splitters, or the nosology of genetic disease.Perspect Biol Med. 1969; 12: 298-312PubMed Google Scholar The lumper and splitter controversies have often been resolved only by molecular elucidation at the DNA level. It turned out that both the lumpers and the splitters were in part correct. Molecular elucidation revealed numerous instances of "many from one" (multiple phenotypes from different mutations in the same gene) and "one from many" (the same phenotype from mutations in two or more separate genes). The main principles of clinical genetics are pleiotropism, genetic heterogeneity, and variation. Pleiotropism—multiple phenotypic effects of a single mutant gene, the basis of syndromes—mandates lumping of disorders that may have been separately described on the basis of features that predominate in one group of patients. Genetic heterogeneity, however recognized, is a basis for splitting. Some aspects of variation will be discussed later, in connection with multifactorial inheritance. With molecular characterization of an increasing number of genetic disorders through gene mapping followed by positional cloning, genetic heterogeneity independent of phenotypic heterogeneity has been recognized as more frequent than previously realized. When the causative mutations are at different genes/loci, OMIM now considers the disorders to be distinct entities. See, for example, the several forms of long QT syndrome: LQT1 (MIM #192500), LQT2 (MIM +152427), LQT3 (MIM #603830), LQT4 (MIM #600919), LQT5 (MIM +176261), LQT6 (MIM +603796), and LQT7 (MIM #170390). Often, the phenotype can be discerned to be somewhat different when the molecular characterization permits the study of "pure-culture" groups of cases. Additionally, treatment of the disorder may be found to be specific to the underlying genetic basis. "Many from one," different phenotypes with different mutations in the same gene, is illustrated by many examples. The multiple disorders resulting from mutations in HBB, a total of at least seven, represents an early example. The multiple disorders resulting from mutations in the lamin A/C gene (LMNA [MIM *150330])—a total of at least 11, varying from progeria (MIM #176670) to a form of Charcot-Marie-Tooth disease (MIM #605588)—provide an impressive recent example. In general, usage has dictated the choice of the preferred designations for disorders. The preferred designations change over time, as popular usage changes; "mucoviscidosis" became "cystic fibrosis of the pancreas" and then simply "cystic fibrosis." Usage (in the choice of particular eponyms, for example) tended to vary some between the United States and Europe, but this is now much less the case. The preferred designations in OMIM have increasingly been used as a standard in publications, along with the inclusion of OMIM entry numbers. All alternative designations of both phenotypes and genes, including historical ones, are usually listed in the heading of each entry. The initial choice of names for "new" genetic disorders has been chaotic. In some instances, one feature of a pleiotropic syndrome was selected to designate the whole; examples include arachnodactyly for Marfan syndrome (MIM #154700) and angiokeratoma for Fabry disease (MIM #301500). However, often, over time, a constellation of features was found to be more important to clinical diagnosis than was a single feature. Partly for this reason, eponymic designations have been used heavily and have much to recommend them. They have the advantage of conveying no preconceived notion as to the basic nature of the abnormality. "Hurler syndrome" was, time showed, a better designation than was "lipochondrodystrophy," which Index Medicus continued to use long after the fundamental fault was found to concern mucopolysaccharides, not lipid. The eponym is merely a "handle." Often the person whose name is used was not the first to describe the disorder or did not describe the full syndrome as it subsequently came to be known. Priority disputes I have never considered important; when it is found that Jones in fact described a disorder before Smith, it seems pointless to change from a widely established use of the Smith eponym. MIM/OMIM has consistently used the nonpossessive form of eponyms—for example, "Marfan syndrome," not "Marfan's syndrome." In this practice, I was schooled by J. Earle Moore and others who edited the first edition (1956) of my "Heritable Disorders of Connective Tissue"21McKusick VA Heritable disorders of connective tissue. 1st ed. Mosby, St. Louis1956Google Scholar and used the then-current edition of the AMA Manual of Style. Among other advantages, use of the nonpossessive avoids the mistake of putting an apostrophe in the wrong place, writing, for example, "Wilm's tumor" for "Wilms tumor" and "Grave's disease" for "Graves disease." It has been useful in speech and writing to have acronyms pronounced as single words, for example, TAR syndrome (MIM #274000) for thrombocytopenia–absent radius syndrome, and VATER association (MIM 192350) for vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial dysplasia. Initialisms, such as OFD1 (MIM #311200)–OFD10 (MIM 165590) for orofaciodigital syndromes, have also been useful. Family initials, however, as in the Opitz G/BBB syndrome (MIM #300000), have been abandoned as a method of naming. Geographic designations are sometimes used—for example, familial Mediterranean fever (MIM #249100 and MIM #134610) and Tangier disease (MIM #205400), but these can prove a problem when populations outside the originally described regions are found to have the disease. In some cases, the nature of the basic defect is used as the name. Factor VIII deficiency (hemophilia A [MIM +306700]) and G6PD deficiency (MIM #305900) are examples. In some ways, this has advantages, but the disadvantage is indicated by the absence of clinical specificity; there are, for example, a considerable number of different forms of G6PD deficiency, in terms of clinical presentation. Pejorative or demeaning designations have always been discouraged.22Feingold M The use of inappropriate, demeaning, and pejorative terminology to describe syndromes.Am J Med Genet A. 2006; 140: 410-411Crossref PubMed Scopus (4) Google Scholar, 23Cohen Jr, MM Problems in
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