When McKusick established his medical genetics program and clinic in 1957, the structure of DNA and its mechanism for transmitting genetic instructions were only beginning to be understood; recombinant DNA and gene sequencing technologies were several decades from realization. The chromosomes could be visualized with the microscope but not very well. Immunologists had delineated blood groups as genetic markers, and biochemists were rapidly expanding the understanding of certain metabolic disorders. However, the knowledge base of medical genetics was built largely through the collection and collation of thousands of medical case histories, and the cataloging of hundreds of individual inherited disorders and their variations.
Genetic disorders are usually recessive traits, i.e., their manifestations in the general population are relatively rare. Thus, the case literature and "clinical material" available to researchers is quite limited, compared to what is available for studying more common diseases. To establish and expand the new field of medical genetics, McKusick and his team needed to amass cases from both the medical literature and their own clinical work. McKusick, of course, had been collecting and documenting cases of inherited connective tissue disorders for over a decade. As director of the Moore Clinic, he organized a monthly journal club, whose members combed the medical and scientific literature for case studies and research relevant to medical genetics. These references, published annually (1958-1964) as one month's issue of the Journal of Chronic Diseases, included annotations by McKusick's team and illustrations and short reports from their own clinical practice. The Moore Clinic increasingly attracted patients via other Hopkins departments, outside medical referrals, and even by word of mouth from the patients themselves. By 1960, however, McKusick knew that sitting in the clinic waiting for patients to come to him would make for slow progress. Much more data could be gleaned from field work with reproductively isolated populations, where recessive genes are manifested more often. McKusick had been looking for just such a group to study when, in 1962, two things directed his attention to the Amish. The first was an article that mentioned high rates of dwarfism in the Amish of Lancaster County, Pennsylvania. The second was a proposal submitted to the Johns Hopkins University Press by sociologist John Hostetler for a book examining the medical, social, and cultural beliefs of the Old Order Amish. Hostetler's work indicated that the Amish would be an ideal population to study for many reasons: it is a well-defined and largely closed population, derived from a relatively small number of immigrant ancestors; families are large and the average level of intermarriage is high; standards of medical care are high, and the Amish utilize regular physicians and clinics as well as folk healers, so there are medical records available; poor nutrition and infectious disease do not confuse interpretation of findings; socioeconomic circumstances are fairly uniform among the group, reducing this source of variability; as an agrarian people, the Amish are geographically stable, and large kindreds are available for study in a limited area; Amish families keep well-informed of illness in groups throughout the country by means of a weekly newspaper, The Budget, among other things; and Amish genealogical records are excellent.
With the help of Hostetler and a small number of physicians who treated Amish patients, McKusick and his research team surveyed hundreds of local physicians about cases of hereditary anomalies among their Amish patients, and visited those patients and their families. Within the first year, they had found a rare form of dwarfism, Ellis-van Creveld syndrome (EVC) in more than fifty patients; their findings doubled the total reported cases of EVC in the scientific literature. They also identified a new form of recessive dwarfism--cartilage-hair hypoplasia--in fifty Amish families. And they disproved reports that mental retardation was one feature of EVC. During the next few years McKusick's team developed an impressive range of sources to track down specific forms of genetic disease among the Amish and their ancestors: public records, hospital records, newspapers, genealogy books, and contacts with parents, teachers, physicians and nurses, midwives, and even undertakers. They examined patients with hereditary disorders and gathered samples of blood, tissue, and urine to be analyzed for other possible inherited patterns such as blood groups or inborn errors of metabolism. They also gathered information about stillborn children and those who had died in infancy, because inherited disorders often resulted in early death.
McKusick's group had pioneered the use of computer programs for doing linkage analysis (which depended on measuring statistical frequencies of inherited traits) and was able to apply computer techniques to the Amish study as well. Studies of the Amish by McKusick and his research fellows continued for several decades, expanding beyond Pennsylvania communities to include those in Ohio and Indiana, and generating both research methods and new knowledge. In 1965, McKusick attended the national convention of Little People of America (LPA), a support organization for people with dwarfism. Subsequent collaboration between McKusick's team and LPA members greatly extended the study of inherited skeletal abnormalities, and McKusick was made an honorary life member of LPA in 1970.
The Amish study also contributed indirectly to the development of one of McKusick's most notable achievements, Mendelian Inheritance in Man (MIM). In the early 1960s, McKusick published a lengthy article on the X-chromosome, then the only human chromosome to which specific traits had been mapped. He discussed recent discoveries on the topic and listed the 60 known X-linked traits. For each trait, he provided the preferred designation, a description of the trait, and detailed information on its genetics, with bibliographic references. Because the Amish study promised to reveal new recessive disorders, McKusick and his team compiled a catalog of known recessive disorders to use as a reference. By 1963, McKusick had decided to cease the annual reviews of medical genetics, and incorporate them into a comprehensive, regularly updated catalog of Mendelian phenotypes, both recessive and dominant, using the format employed in his work on the X-chromosome. This would enable practitioners and researchers to readily find current information about rare inherited disorders when they encountered them. The first edition of MIM was published in 1966, with 1,486 entries, mostly for genes mapped through linkage studies. Starting in the late 1960s, entries were also created in MIM for individual genes for which no associated Mendelian phenotype was known. Somatic cell hybridization (a technique for isolating individual human chromosomes from cultures of fused mouse and human cells) had made it possible to locate genes on human chromosomes without using family linkage maps; subsequent advances in DNA technologies have greatly expanded the catalog, which contained listings for over 12,000 genes of known sequence and over 6,000 phenotypes by late 2008.
The catalog data was kept on a computer database starting in 1964, to simplify indexing and publication, and reduce errors during updates. During the 1980s, MIM was adopted by the National Library of Medicine (NLM) 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. An online version of the 6th edition of MIM (1983) with updates and with the IRx search engine was demonstrated at the Bar Harbor course in 1985 and used as a resource at the eighth Human Gene Mapping workshop in Helsinki later that summer. By the fall of 1985, an online version of MIM, now called "OMIM" became a major aid in authoring and editing the catalog. Beginning in September 1987, OMIM was made generally accessible on the Internet from the Welch Medical Library at JHU. The informatics aspects of OMIM were transferred to the National Center for Biotechnology Information (NCBI) of the NLM in December 1995 (editing is still done at Johns Hopkins). The twelfth and last print edition of MIM was published in 1998. MIM and its online incarnation have become the standard reference work on current knowledge not just about genetic disorders, but about the genome as a whole. McKusick continued to devote much of his time to this enormous project until several years before his death.