PMC:1852721 / 34596-42049 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":"A Garrodian Perspective on MIM/OMIM\n\n“The Lessons of Rare Maladies”\nIn 1956, I dedicated the first edition of my Heritable Disorders of Connective Tissue 21 to Archibald Garrod “and to all who believe, as he did, that the clinical investigation of hereditary disorders can shed light on normal developmental and biochemical mechanisms.” (The dedication was accompanied by a previously unpublished etching of Garrod in academic garb by T. Binney Gibbs [created in 1922]. This was provided to me by Garrod’s daughter, distinguished Cambridge University archeologist Dorothy A. E. Garrod.) The preface of Heritable Disorders of Connective Tissue reproduced the now-well-known quotation from a letter written (in Latin) by William Harvey in 1657 that Garrod included (in translation) in his paper entitled “The lessons of rare maladies” published in Lancet in 192831:\nNature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature by careful investigation of cases of rarer forms of disease. For it has been found, in almost all things, that what they contain of useful or applicable nature is hardly perceived unless we are deprived of them, or they become deranged in some way.\nThis Harveian/Garrodian principle has been extensively documented in the case of rare genetic syndromes. The many rare disorders cataloged in OMIM are “experiments of nature” with much to teach about normal biochemical, developmental, and physiologic mechanisms, and indeed much has been learned from them, especially in the 20+ years since the first “disease gene” identified by positional cloning was recorded in OMIM.\nIncreasingly, basic scientists turn to the human for exploration of the significance of findings in experimental systems or look for “human models” of phenotypes or phenomena in Caenorhabditis elegans, Drosophila, mouse, and other experimental species. The researcher asks, “Has a defect related to ‘my' gene or protein been identified in the human?” OMIM has proved a useful way to find human models of “disorders” in experimental organisms.\nA human-interest story in this connection involves the late Robert J. Gorlin (1923–2006) and his son Jed B. Gorlin. Jed cloned the filamin A gene (FLNA [MIM +300017]) in 199032 and mapped it to Xq28 in 1993.33 It was of particular delight to his father when FLNA was found (by others) to be the site of mutations underlying frontometaphyseal dysplasia (FMD [MIM #305620]), otopalatodigital syndrome (OPD1 [MIM #311300]), and several other disorders for which the father had provided definitive clinical descriptions as well as names.\n\nGarrod’s Generalization: Most Diseases Are Related to Chemical Individuality\nThe title of Garrod’s landmark report on the first of his inborn errors of metabolism was “The Incidence of Alkaptonuria, a Study in Chemical Individuality.”34 By “incidence,” he meant occurrence, and, in the work, he referred particularly to the role of parental consanguinity. In one short work, he identified consanguinity as a prime factor in the occurrence of rare recessive disorders and introduced his concept of chemical individuality.\nIn Inborn Factors in Disease, a monograph published in 1931, Garrod35 generalized his concept of chemical individuality to encompass all disease, including common disorders. His thinking was rediscovered by Charles Scriver and Barton Childs, who, in 1989, published a facsimile edition of the 1931 monograph, with commentary.36 They pointed out that the substance of Garrod’s thesis is contained in the following summarizing paragraph at the end of his 1931 “essay”35(p 157):\nIt might be claimed that what used to be spoken of as a diathesis is nothing else but chemical individuality. But to our chemical individualities are due our chemical merits as well as our chemical shortcomings; and it is more nearly true to say that the factors which confer upon us our predispositions to and immunities from the various mishaps which are spoken of as diseases, are inherent in our very chemical structure and even in the molecular groupings which confer upon us our individualities, and which went to the making of the chromosomes from which we sprang.\nLargely on the basis of Garrodian thinking, Childs, in 1999,37 developed what he called “a logic of medicine,” defining logic as a statement of the formal principles underlying a branch of knowledge. From these analyses came a vision of individualized medicine—a brand of medicine designed to match the uniqueness of the individual and encompassing all disease, including common disease. Despite its title Mendelian Inheritance in Man, there are reasons why identifiable genetic factors in all disease including those that are not strictly Mendelian should be included in OMIM (see below). These are the common disorders previously labeled “multifactorial” and now usually termed “complex traits” (or disorders). The more we know about classic Mendelian disorders, the more we realize that these are also complex; see the example of glycerol kinase deficiency (MIM #307030).38 Conversely, Mendelian subtypes of common complex disorders have come to light.\nMost forms of cancer are clearly multifactorial, indeed multigenic. All are fundamentally genetic, based on changes in the genetic material; for the most part, they are somatic genetic disorders. Epigenetic changes are also importantly involved, as discussed below. In many sporadic forms of cancer, multiple genes have been identified as playing a role in initiation, progression, invasion, metastasis, and resistance to therapy. OMIM records these somatic mutations among AVs. Somatic mutations related to prostate cancer (MIM #176807) are recorded for at least eight genes and, in the case of some of these genes, both familial and sporadic forms of prostate cancer are represented. Colorectal cancer (MIM #114500) displays an even more extensive array of genes involved in familial and/or sporadic forms.\nIn several instances, the gene mutant in familial cancer syndromes has been found to undergo somatic mutation to cause sporadic cancer of the type featured in the familial cancer syndrome. The APC gene (MIM +175100) mutant in adenomatous polyposis coli is importantly involved in sporadic colorectal cancer, and somatic mutations in APC have been found also in sporadic gastric cancer (MIM +175100.0010), sporadic hepatoblastoma (MIM +175100.0024), and other sporadic cancers. The VHL gene (MIM *608537) is mutant in von Hippel-Lindau syndrome (MIM #193300), which has renal cancer, pheochromocytoma, and cerebellar hemangioblastoma as components; it is implicated also in sporadic cases of these three neoplasms. Germline mutations in the TP53 gene (MIM +191170), somatic mutations of which have been identified in a variety of cancers, are the basis for one form of the Li-Fraumeni family cancer syndrome (LFS1 [MIM #151623]) that combines malignancies of a variety of tissue types, most often soft-tissue sarcomas, osteosarcomas, and breast cancer. (Li-Fraumeni syndrome is genetically heterogeneous; in addition to the LFS1 form caused by mutations in TP53, another form, LFS2 [MIM #609265], is caused by mutations in the CHEK2 gene [MIM *604373], and a third form, LFS3 [MIM %609266], maps to a locus on 1q23.)","divisions":[{"label":"title","span":{"begin":0,"end":35}},{"label":"sec","span":{"begin":37,"end":2802}},{"label":"title","span":{"begin":37,"end":67}},{"label":"p","span":{"begin":68,"end":863}},{"label":"p","span":{"begin":864,"end":1404}},{"label":"p","span":{"begin":1405,"end":1825}},{"label":"p","span":{"begin":1826,"end":2268}},{"label":"p","span":{"begin":2269,"end":2802}},{"label":"title","span":{"begin":2804,"end":2880}},{"label":"p","span":{"begin":2881,"end":3324}},{"label":"p","span":{"begin":3325,"end":3800}},{"label":"p","span":{"begin":3801,"end":4372}},{"label":"p","span":{"begin":4373,"end":5328}},{"label":"p","span":{"begin":5329,"end":6137}}],"tracks":[{"project":"2_test","denotations":[{"id":"17357067-2391361-2054052","span":{"begin":2439,"end":2445},"obj":"2391361"},{"id":"17357067-8406501-2054053","span":{"begin":2476,"end":2478},"obj":"8406501"},{"id":"17357067-11479736-2054054","span":{"begin":5247,"end":5249},"obj":"11479736"}],"attributes":[{"subj":"17357067-2391361-2054052","pred":"source","obj":"2_test"},{"subj":"17357067-8406501-2054053","pred":"source","obj":"2_test"},{"subj":"17357067-11479736-2054054","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93ecd4","default":true}]}]}}