J Med Genet 1993; 30: 1-26 I REVIEW ARTICLE The morbid anatomy of the human genome: chromosomal location of mutations causing disease Victor A McKusick, Joanna S Amberger Abstract Title - name of gene locus. Information is given in tabular form de- MIM# - This is the number in McKusick's rived from a synopsis of the human gene Mendelian Inheritance in Man, 10th ed (1992) map which has been updated continu- and its continuously updated online version ously since 1973 as part of Mendelian OMIM. (For historical reasons, the number Inheritance in Man Johns Hopkins may sometimes indicate location ofthe entry in University Press, 10th ed, 1992) and of the 'dominant catalogue' because the wildtype OMIM (Online Mendelian Inheritance in gene was characterised and mapped before the Man, available generally since 1987). The recessive disorder resulting from mutation at part of the synopsis reproduced here that site. The practice is to create only one consists of chromosome by chromosome entry in OMIM for each gene locus.) gene lists of loci for which there are asso- ciated disorders (table 1), a pictorial rep- resentation of this information (fig la-d), and an index of disorders for which the Method of mapping causative mutations have been mapped A = in situ DNA-RNA or DNA-DNA anneal- (table 2). ing ('hybridisation'), for example, ribosomal In table 1, information on genes that RNA genes to acrocentric chromosomes; have been located to specific chromoso- kappa light chain genes to chromosome 2. mal positions and are also the site of AAS = deductions from the amino acid disease producing mutations is arranged sequence of proteins, for example, linkage by chromosome, starting with chromo- of delta and beta globin loci from study of some 1 and with the end of the short arm hemoglobin Lepore. of the chromosome in each case. C = chromosome mediated gene transfer In table 2 an alphabetised list of these (CMGT), for example, cotransfer of galacto- disorders and the chromosomal location kinase and thymidine kinase. of the mutation in each case are pro- Ch = chromosomal change associated with vided. Both in the 'Disorder' field of table particular phenotype and not proved to repre- 1 and in table 2, the numbers 1, 2, or 3 in sent linkage (Fc), deletion (D), or virus effect parentheses after the name of the dis- (V), for example, loss of 13q14 band in some order indicate that its chromosomal cases of retinoblastoma. location was determined by mapping of the wildtype gene (1), by mapping of D = deletion or dosage mapping (concurrence the clinical phenotype (2), or by both of chromosomal deletion and phenotypic evid- strategies (3). ence of hemizygosity), trisomy mapping (pres- (J Med Genet 1993;30:1-26) ence of three alleles in the case of a highly polymorphic locus), or gene dosage effects (correlation of trisomic state of part or all of a The fields in the listing by chromosome (table chromosome with 50% more gene product). 1) are as follows: Includes 'loss of heterozygosity' (loss of alleles) in malignancies. Examples: acid phos- Location - that is, chromosomal site phatase- 1 to chromosome 2; glutathione Center for Medical = = Genetics, The Johns (p short arm; q long arm; numbers = band; reductase to chromosome 8. Includes DNA Hopkins University ter = end). dosage, for example, fibrinogen loci to 4q2. School of Medicine, Blalock Building, Symbol - The symbol approved by the Dosage mapping also includes coamplification Room 1007, 600 N Nomenclature Committee of the Human Gene in tumour cells. Wolfe Street, Mapping Workshops and their successor orga- Baltimore, MD EM= exclusion mapping, that is, narrowing 21287-4922, USA. nisation is given first; alternative symbols are the possible location of loci by exclusion of V A McKinsick included. parts of the map by deletion mapping, extended J S Amberger Status - C = confirmed; P = provisional; to include negative lod scores from families Correspondence to L= 'in limbo' (that is, tentative or inconsis- with marker chromosomes and negative lod Dr Amberger. tent). The 'in limbo' entries are not listed in scores with other assigned loci, for example, Received 12 October 1992. fig 1. support for assignment of MNSs to 4q. 2 McKusick, Amberger F = linkage study in families, for example, X/A = X-autosome translocation in female linkage of ABO blood group and nail-patella with X linked recessive disorder, for example, syndrome. (When a chromosomal heteromor- assignment of Duchenne muscular dystrophy phism or rearrangement is one trait, Fc is used, to Xp2l. for example, Duffy blood group locus on chro- Disorder - Allelic disorders are separated by mosome 1. When one or both of the linked loci semicolons. Brackets [ ] indicate a 'non- are identified by a DNA polymorphism, Fd is disease', that is, a variation with no definite used, for example, Huntington's disease on adverse consequences. Braces { ' indicate spe- chromosome 4. F = L in the HGM work- cific susceptibility or resistance with mono- shops.) genic basis. (1) = wildtype gene mapped. H = based on presumed homology, for (2) = disease phenotype mapped. (3) = both example, proposed assignment of TF to 3q. wildtype gene and disease phenotype mapped. Mainly heuristic or confirmatory. Mouse - Mouse chromosome carrying homo- HS = DNA/cDNA molecular hybridisation in logous gene. solution ('Cot analysis'). References for the mapping information and L = lyonisation, for example, OTC to X chro- additional information about the loci and dis- mosome. (L = symbol for family linkage study orders are provided in Mendelian Inheritance in the HGM workshops.) in Man, 10th ed (McKusick, 1992) and OMIMT (Online Mendelian Inheritance in LD = linkage disequilibrium, for example, Man). To obtain information on accessing beta and delta globin genes. OMIM, contact: M = Microcell mediated gene transfer (MMGT), In the United States: GDB/OMIM User for example, a collagen gene (COLlAl) to Support, Welch Medical Library, 1830 E chromosome 17. Monument Street, 3rd Floor, Baltimore, MD OT = ovarian teratoma (centromere mapping), 21205, USA (Telephone: 410-955-7058, Fax: for example, PGM3 and centromere of chro- 410-955-0054, e-mail: help(a welch.jhu.edu). mosome 6. In the United Kingdom: Christine Bates, Human Gene Mapping Program Resource Pcm = PCR of microdissected chromosome Centre, CRC, Watford Road, Harrow, Middx segments (see REI). HAl 3UJ, UK (Telephone: 44-81-869-3446, Psh = PCR of somatic cell hybrid DNA. Fax: 44-81-869-3807, e-mail: cbates(@uk.ac.crc). In Germany: Otto Ritter, German Cancer R = radiation hybrids, that is, irradiation of Research Centre (DKFZ), Molecular Bio- cells followed by 'rescue' through fusion with physics Group, Im Neuenheimer Feld 280, non-irradiated (non-human) cells (Goss-Har- D-6900 Heidelberg 1, FRG (Telephone: ris method of radiation-induced gene segrega- 49-6221-42-2372, Fax: 49-6221-40-1271, tion), for example, order of genes on Xq. e-mail: dok261 (a cvxl 2.dkfz-heidelberg.de). RE= restriction endonuclease techniques, for In Australia: Alex Reisner, ANGIS, Electri- example, fine structure map of the beta globin cal Engineering Building, J03, University of cluster (HBBC) on I lp; physical linkage of 3 Sydney, Sydney, NSW 2006, Australia, (Tele- fibrinogen genes (on 4q). phone: 61-2-692-294, Fax 61-2-692-3847, REa = combined with somatic cell hybridis- e-mail: reisner([email protected]). ation, for example, NAG (HBBC) to lip. REb = combined with chromosome sorting, for example, insulin to 1 lp. Includes Lebo's Discussion adaptation (dual laser chromosome sorting In these listings, 738 disorders in total are and spot blot DNA analysis), for example, indicated as assigned to specific chromosomes MGP to 1 q. (For this method, using flow and, in most instances, to specific regions of sorted chromosomes, W was the symbol those chromosomes. (More than 50 other dis- adopted by the HGM workshops.) orders are known to be caused by mutations in REc = hybridisation of cDNA to genomic genes on the X chromosome but their regional fragment (by YAC, PFGE, microdissection, location is not known and therefore they have etc), for example, A-11 on Xq. not been included here.) The 738 disorders are REl = isolation of gene from chromosome distributed over 625 loci; many loci have more specific genomic library (see Pcm). than one allelic mutation producing distinct REn = neighbour analysis in restriction phenotypes. for in field Some of the disorders (labelled with the fragments, example, pulsed gel number 1) have been mapped to specific sites electrophoresis (PFGE). by virtue of mapping of the wildtype gene; S = 'segregation' (cosegregation) of human cel- many forms of chronic non-spherocytic hae- lular traits and human chromosomes (or seg- molytic anaemia such as those due to pyruvate ments of chromosomes) in particular clones kinase deficiency, triosephosphate isomerase from interspecies somatic cell hybrids, for ex- deficiency, and bisphosphoglycerate mutase ample, thymidine kinase to chromosome 17. deficiency are examples. When with restriction enzyme, REa; with Other disorders (labelled with the number hybridisation in solution, HS. 2) are mapped only on the basis of the clinical V = induction of microscopically evident chro- phenotype which is found to be linked to mosomal change by a virus, for example, ade- markers at a particular chromosomal site or novirus 12 changes on chromosomes 1 and 17. the phenotype is found in association with a The morbid anatomy of the human genome 3 chromosomal aberration. Huntington's disease neoplasia type II are possible examples. Close is an example of a disorder mapped by linkage linkage of mutant genes, each responsible for a to DNA markers. specific component, in general is rejected as Yet other disorders (labelled with the the cause of genetic syndromes, in favour of number 3) have been mapped by both pleiotropism. The bona fide nature of some so approaches. The form of elliptocytosis due to a called contiguous gene syndromes is unques- defect in the gene encoding protein 4.1 is an tionable, however.