JMed Genet 1994;31:265-279 265 Review article J Med Genet: first published as 10.1136/jmg.31.4.265 on 1 April 1994. Downloaded from The morbid anatomy of the human genome: chromosomal location of mutations causing disease (update 1 December 1993) Victor A McKusick, Joanna S Amberger A survey of the chromosomal location of Title - name of gene locus mutations causing genetic disorders was pub- MIM# - This is the number in McKusick's lished in this journal in January 1993 Mendelian inheritance in man (MIM, 10th ed, (McKusick and Amberger, 1993). The infor- 1992), its continuously updated online version mation presented then was complete to OMIM, and its periodically released CD- 1 November 1992. Here, we present informa- ROM version. (For historical reasons, the tion that has become available since that date, number may sometimes indicate location of including both new assignments and revision the entry in the "dominant catalogue" because of previous assignments. This information on the wild type gene was characterised and the so-called morbid anatomy of the human mapped before the recessive disorder resulting genome is derived from a synopsis of the from mutation at that site. The practice has human gene map that has been updated con- been to create only one entry in MIM for each tinuously since 1971 as part of McKusick's gene locus; however, for some disorders, an Mendelian inheritance in man (10th ed, 1992) entry describing the phenotype, identified by a and of OMIM (online Mendelian inheritance in number sign (#), and a separate entry, identi- man, available generally since 1987). fied by an asterisk, for the protein affected by In table 1, new information on genes that the mutation have been created. Marfan syn- have been located to specific chromosomal drome (154700) and fibrillin (134797) are positions and are also the site of disease-pro- examples; see chromosome 15.) ducing mutations is arranged by chromosome, http://jmg.bmj.com/ starting with chromosome 1 and with the end Method of mapping of the short arm of the chromosome in each A = in situ DNA-RNA or DNA-DNA case. The new information is presented in pic- annealing ("hybridisation"); for example, torial form in the figure. COL7A1 to 3p21.3 2. In table 2 an alphabetised list of these disor- C = chromosome mediated gene transfer ders and the chromosomal location of the (CMGT); for example, cotransfer of COLlAl mutation in each case are provided. After the and kinase thymidine gene on chromosome 17. on September 27, 2021 by guest. Protected copyright. name of the disorder, both in the "Disorder" Ch = chromosomal change associated with field of table 1 and in table 2, the numbers 1, particular phenotype and not proved to repre- 2, or 3 in parentheses indicate that its chromo- sent linkage (Fc), deletion (D), or virus effect somal location was determined by mapping of (V); for example, blepharophimosis, epican- the wild type gene (1), by mapping of the clin- thus inversus, and ptosis to 3q22-q23. ical phenotype (2), or by both strategies (3). D = deletion or dosage mapping (concur- (In some instances, a (3) is used when the rence of chromosomal deletion and phenotyp- clinical phenotype has been mapped and an ic evidence of hemizygosity), trisomy mapping intragenic mutation has been identified in a (presence of three alleles in the case of a highly candidate gene even though the wild type gene polymorphic locus), or gene dosage effects has not been independently mapped.) (correlation of trisomic state of part or all of a The fields in the listing by chromosome chromosome with 50% more gene product). (table 1) are as follows: Includes "loss of heterozygosity" (loss of alle- Location - that is, chromosomal site (p = les) in malignancies. Examples: acid phos- Center for Medical short arm; q = long arm; numbers = band; ter phatase-I to chromosome 2; glutathione Genetics, = end). reductase to chromosome 8. Includes DNA The Johns Hopkins Symbol - The symbol approved by the Hospital, dosage; for example, fibrinogen loci to 4q2. Blalock Building, Nomenclature Committee of the Human Dosage mapping also includes coamplification Room 1007, Gene Mapping Workshops and their successor in tumour cells. 600 N Wolfe Street, organisation is given first; alternative symbols F = linkage study in Baltimore, MD families; for example, 21287-4922, USA are included. linkage of ABO blood group and nail-patella VA McKusick Status - C = confirmed; P = provisional; L syndrome. When a chromosomal heteromor- J S Amberger = "in limbo" (that is, tentative or inconsis- phism or rearrangement is one trait, Fc is Correspondence to tent). The "in limbo" entries are not included used; for example, Duffy blood group locus J S Amberger in the figure. on chromosome 1. When one or both of the 266 McKusick, Amberger linked loci are identified by a DNA polymor- the number 2) that have been mapped only on phism, Fd is used; for example, Osler-Rendu- the basis of the clinical phenotype, which is Weber disease on chromosome 9q. F=L in found to be linked to markers at a particular the symbolism of the HGM workshops. chromosomal site or is found in association J Med Genet: first published as 10.1136/jmg.31.4.265 on 1 April 1994. Downloaded from H = based on presumed homology; for with a chromosomal aberration, include alkap- example, Neimann-Pick disease, type C, on tonuria, cartilage-hair hypoplasia, familial l9p. Mainly heuristic or confirmatory. dysautonomia, hereditary haemorrhagic LD = linkage disequilibrium; includes telangiectasia, and Werner syndrome. homozygosity mapping, for example, familial Rubinstein-Taybi syndrome was mapped on dysautonomia. the basis of a chromosomal aberration. The M = Microcell mediated gene transfer mapping information provides the starting (MMGT); for example, Bloom syndrome. point for isolating the mutant gene by posi- Psh = PCR of somatic cell hybrid DNA. tional cloning or the candidate gene approach. RE = Restriction endonuclease techniques; In the case of yet other disorders (labelled for example, physical linkage of 3 fibrinogen with the number 3) the clinical disorder and genes (on 4q) and apolipoprotein cluster, the wild type gene have been separately including APOC3 on 1 1q. mapped. These include instances in which the REa = combined with somatic cell hybridis- candidate gene approach has led to definition ation; for example, gene for type VII collagen of the basic defect in the clinical disorder. (COL7A1), which is mutant in dystrophic epi- Examples in the last year included familial dermolysis bullosa. amyotrophic lateral sclerosis, type I (wild type REb = combined with chromosome sorting; gene = SOD1), supravalvar aortic stenosis for example, thyroglobulin to 8q. (For this (wild type gene = elastin), stenosis of the method, using flow sorted chromosomes, W aqueduct of Sylvius (wild type gene = was the symbol adopted by the HGM work- LI CAM), X linked Charcot-Marie-Tooth shops.) disease (wild type gene = connexin-32), and REn = neighbour analysis in restriction X linked immunodeficiency with hyper-IgM fragments, for example, in pulsed-field gel (wild type gene = CD40 ligand). electrophoresis (PFGE); for example, protein Mapping of genetic disorders has shed light C inhibitor. on both allelism and non-allelism. Examples S = 'segregation' (cosegregation) of human of non-allelic genetic heterogeneity found or cellular traits and human chromosomes (or extended in the last year include the following: segments of chromosomes) in particular the number of distinguished types of Charcot- clones from interspecies somatic cell hybrids; Marie-Tooth disease were increased by the for example, GM2 ganglioside activator pro- mapping of forms to Ip and 8q; in addition to tein on chromosome 5. When with restriction the forms already mapped, two types of famil- enzyme, REa. ial hypertrophic cardiomyopathy were mapped Disorder - Allelic disorders are separated to chromosomes 15 and 11; a third form of http://jmg.bmj.com/ by semicolons. Brackets [] indicate a "non- spinocerebellar ataxia was located to chromo- disease", that is, a variation with no definite some 14; non-allelic heterogeneity in multiple adverse consequences. Braces { } indicate spe- exostoses and Wagner syndrome was estab- cific susceptibility or resistance with mono- lished by finding linkage in some families to genic basis. (1) = wild type gene mapped. (2) chromosome 8 or 12, respectively, but not in = disease phenotype mapped. (3) = both wild others. The practice is to assign a number to type gene and disease phenotype mapped (or the various types of a particular disorder as on September 27, 2021 by guest. Protected copyright. disease phenotype mapped and mutations they are defined; for example, CMH1-4 for identified in the wild type gene). the forms of hypertrophic cardiomyopathy. Mouse - Mouse chromosome carrying The number of forms of retinitis pigmentosa homologous gene. defined on the basis of linkage has now reached RP10. As soon as the nature of the Discussion gene that is mutated is identified, one can sub- With the additions made in the last year, a stitute for the number a designation such as total of 928 disorders have by now been "retinitis pigmentosa, rhodopsin-related" or assigned to specific chromosomes and, in most "retinitis pigmentosa, peripherin-related." instances, to specific regions of those chromo- Allelic series as the basis of phenotypic somes. (More than 50 other disorders are diversity, that is, allelic heterogeneity, is illus- known to be caused by mutations in genes on trated by pairs or sets of phenotypes such as the X chromosome but their regional location cystic fibrosis and congenital bilateral absence is not known and therefore they have not been of vas deferens (caused by mutation in the included in this count.) The 928 disorders are CFTR gene) and the some seven disorders distributed over 767 loci; many loci have more that have been related to mutations in the type than one allelic mutation producing distinct II collagen gene.