Connecting Phenes with Genes in MIM/OMIM
Genetics was defined by William Bateson as the science of biologic variation. It can also be defined simply as the study of inheritance, and genomics as the study of genomes.26 However genetics is defined, one of its main objectives is to identify specific genetic elements underlying specific phenotypes—to connect phene and gene. The first of the three original phenotype catalogs, that for the X chromosome, was published in 19626 as one of three parts of a review “On the X chromosome of Man.” The catalog of X-linked traits was assembled as an assessment of the gene content of the X chromosome. The list of traits, most of them disorders or diseases, was compared to a photographic negative from which a positive picture of the genetic constitution of the X chromosome could be derived. Although the second catalog, that for autosomal recessive traits, was assembled for utilitarian purposes—that is, as a resource in the identification of new recessive diseases in inbred groups such as the Amish—the “gene behind the phene” was always in mind, and no more than one entry per gene was wittingly made from the beginning of MIM in the 1960s. However, in the age before human molecular genetics, the one gene–several phenotypes and one phenotype–several genes complexity meant that the one gene–one entry rule was often on shaky ground.
Connecting phene to gene is particularly important for medical genetics, because definition of the precise mutational lesion allows specific diagnosis. Moreover, it separates homogeneous clusters of cases for evaluation of prognosis and therapy and for elucidation of the steps from gene back to phene that can be important to therapy and prevention.
Mapping the chromosomes—that is, defining the locus of the genetic elements responsible for particular phenomatypes to specific chromosomal sites—was a first step in connecting phene to gene. The mapping process began for the autosomes in 196827 and advanced rapidly in the next 20 years (fig. 4 ). (In 1968, as indicated by the second edition of MIM published that year, 68 phenotypes, judged to be clearly X linked and therefore honored with an asterisk, had been mapped to the X chromosome, but the regional localization on the X chromosome had not yet been established for any of them.)
Figure 4 Growth of information in MIM concerning mapping of genes and genetic loci to specific human chromosomes in the period up to the initiation of the Human Genome (Sequencing) Project. In 1968, when the first gene was assigned to a specific autosome (the Duffy blood group to the centromeric region of chromosome 1),27 MIM recorded 68 X-linked phenotypes with an asterisk, indicating confidence in X-linked inheritance.
As of January 29, 2007, OMIM contained information about 2,002 genes that had at least one disease-related mutation. (That count had reached 1,000 by January 1, 2000.28) These 2,002 are the gene entries with at least one AV. Because many genes have more than one distinct phenotype in their mutational repertoire, the total number of phenotypes that have been tracked to the DNA level was 3,345 (table 2 ). (As noted earlier, this count treats the phenotype as separate if it is caused by a mutation in a different gene.) Thus, on average, 1.7 phenotypes have been related to each of the 2,002 genes. Most of this connecting of phene with specific gene has occurred in the past 20 years. Progress during those years was graphed by Peltonen and McKusick.29 Much of it has been achieved by gene mapping (chromosomal mapping of the locus for the phenotype, to be specific), followed by positional cloning of a previously unknown gene or by the positional candidate-gene approach.
Table 2 Mapping of Clinical Disorders (January 29, 2007)
Mapping Type No. Mapped
Loci associated with disorders 3,003
Disorders mapped by association with the gene product 159
Disorders mapped by linkage 942
Disorders “molecularized” 3,345a
 Total no. of disorders mapped 4,446
a Number of phenotypes labeled with “(3)” in the Disorder field of the Synopsis of the Human Gene Map.
It came as something of a surprise when the complete sequence of the human genome revealed many fewer genes, perhaps by a factor of 10, than might be predicted from the abundance of gene products. That a gene may be subject to mutations that cause diverse phenotypes has a cognate phenomenon: a gene may encode a diversity of gene products through mechanisms of combinatorial alternative splicing, posttranslational modification, and other mechanisms. OMIM attempts to include information about the mechanism of the divergent pathologic phenotypes that occur from mutations in a single gene.
The near ultimate in genotype/phenotype correlation is provided by a few examples in which change in a single codon of a single gene results in the disorder. The phenotype in each case is as stereotypic as the genotype; mutations in other regions of the same gene result in different phenotypes. Striking examples include achondroplasia (MIM #100800) due to the c.1138G→A (Gly380Arg) mutation in the FGFR3 gene (MIM *134934.0001), Hutchinson-Gilford progeria syndrome (MIM #176670) due to the c.1824C→T (Gly608Gly) mutation in the LMNA gene (MIM *150330.0022), and fibrodysplasia ossificans progressiva (MIM #135100) due to the c.617G→A (Arg206His) mutation in the ACVR1 gene (MIM *102576.0001). In the case of achondroplasia, a few cases are due to a different nucleotide substitution in the same codon: c.1138G→C (Gly380Arg [MIM *134934.0002]). Similarly, a mutation in the same codon as is involved in the majority of cases of progeria has been found in some cases of that disorder: G→A (Gly608Ser [MIM *150330.0023]).
In ∼70% of cases, Apert syndrome (MIM #101200) is caused by a c.934C→G (Ser252Trp) mutation in the FGFR2 gene (MIM *176943.0010) and, in rare other cases, by a mutation in the next adjacent codon, c.937C→G (Pro253Arg [MIM *176943.0011]). No phenotypic features distinguishing the two genotypic forms were found.30 As cataloged in OMIM, the FGFR3, LMNA, and FGFR2 genes are also the sites of mutations causing, respectively, 9, 12, and 11 other phenotypically distinct disorders.