Reflecting on his career later, McKusick was fond of saying that he was a "medical nomad" in his early days, shifting his professional focus several times. In truth, his interest in history, genealogy, and genetics--especially as these applied to the practice of medicine--was a consistent element throughout his life, whatever his job title. He chose Johns Hopkins for his medical training partly because he had read about the work of medical historian Henry Sigerist, at the Institute for the History of Medicine. His first published article was a history of Broedel's ulnar palsy, published in the 1949 Bulletin of the History of Medicine, and he always insisted that historical background was an essential part of research in any field of medicine.
McKusick's first study in medical genetics began near the end of his internship in 1947, when a teenage patient came into his care. The young man had very striking melanin spots on his lips and the inside of his mouth, and had a long history of intestinal polyps, which had required repeated surgeries. Within the next year, McKusick saw four other patients with the same combination of polyps and spots, three of them from the same family. Hearing that a Boston physician, Harold Jeghers, had seen five cases of this syndrome, McKusick contacted him, and the two wrote up their findings in the New England Journal of Medicine in 1949. It was clear from their case histories and from a much earlier study by a Dutch physician, J. L. A. Peutz, that the syndrome was inherited, but the tools available for genetic analysis were very limited at the time. Much work had been done in mapping genetic linkages in other organisms, including fruit flies and corn, but there were very few known chromosomal markers for humans; indeed, even visualizing separate chromosomes clearly was still difficult, and the correct number of human chromosomes (46) would not be verified until 1956. One of McKusick's mentors, Bentley Glass, persuaded him that linkage--two separate genes on the same chromosome producing the spots and polyps--was unlikely; pleiotropism--one mutant gene producing several distinct effects--was a better explanation. McKusick later cited Glass's tutelage in the principle of pleiotropism as the most important part of his informal genetics training.
While writing up his first study in medical genetics, McKusick was also training as a cardiologist. After his residency at Hopkins, he fulfilled his service obligation to the Army Student Training Program (which had funded his medical training) by working two years on the cardiovascular unit at the U.S. Public Health Service Marine Hospital in Baltimore. (He worked under Luther L. Terry, who later, as U.S. Surgeon General, would issue the first official report linking cigarette smoking to cancer.) It was an exciting time to be working in cardiology; knowledge of heart function was expanding, aided by new diagnostic technologies, and cardiac surgery was advancing rapidly. At the Marine Hospital, McKusick performed cardiac catheterizations and studied the movement in the heart borders by a new imaging method called electrokymography, becoming well-versed in the mechanics of cardiac function. He published papers on chronic constrictive pericarditis, successful reversal of ventricular fibrillation, the electrocardiographic effects of lithium chloride, and other topics.
During his early faculty years at JHUSM, McKusick pursued a study of heart sounds and murmurs using sound spectrography, which had been developed at the Bell Telephone Laboratory for studying speech sounds. Adapted to cardiac studies, the technology could pick up and record the frequency spectrum of heart sounds, allowing physicians to visualize what they were hearing with their stethoscopes. Though not practical for diagnostic testing, this technology, which McKusick renamed spectral phonocardiography, was an excellent teaching tool, especially for learning about the "musical murmurs" (so-called because of their harmonic patterns.) He used the studies as the basis for a comprehensive treatise on heart sounds titled Cardiovascular Sound in Health and Disease, published in 1958.
McKusick had not sidelined his interest in medical genetics while building his credentials in cardiology, however. In the course of his cardiology practice he encountered Marfan syndrome (first described by a French physician in 1896), a condition characterized by unusual height, abnormally long limbs, dislocation of the eye lenses, and aortic aneurysm and prolapsed heart valves, among other symptoms. McKusick thought it likely that this disease was pleiotropic, resulting from a mutation in a gene that controlled one element of connective tissue common to the various affected body structures. He collected a large number of Marfan patients from the various departments at Johns Hopkins Hospital--ophthalmology, orthopedics, as well as pediatric and adult cardiology--and studied them extensively, and often retrospectively through their hospital records. He also studied their family histories whenever possible, to better document the inheritance patterns of Marfan syndrome.
Fascinated with the explanatory potential of inherited connective tissue disorders, McKusick looked for other conditions that might fit this model, and found four: Ehlers-Danlos syndrome (characterized by hyperextensible skin and joints, easily bruised tissues, etc); osteogenesis imperfecta (often characterized by brittle, porous, easily fractured bones and malformed teeth); Hurler syndrome (often characterized by gargoyle-like facial features, dwarfism, clouding of the cornea, etc.); and pseudoxanthoma elasticum (characterized by progressive formation of dermal plaques and inelastic skin.) In many cases, connective tissue disorders include defects of the heart valves and circulatory system, which brings patients to cardiologists. McKusick published his first paper on Marfan syndrome in 1955 and the first edition of Heritable Disorders of Connective Tissue in 1956.
In 1957, A. McGehee Harvey, chair of the Department of Medicine, asked McKusick to take over the direction of a multifaceted chronic disease clinic at Hopkins that had been developed by J. Earle Moore. The clinic had evolved from a venereal disease clinic that had developed long-term follow-up procedures for studying the neurological and cardiovascular manifestations of late syphilis, and the efficacy of pre-penicillin therapies. The clinic had close links to the Johns Hopkins School of Public Health, including the statistics and epidemiology departments, and to the department of public health administration. It also had good sources of research funding for the study of chronic diseases. McKusick, arguing that inherited conditions are the ultimate chronic diseases, agreed to become the clinic's director on the condition that it could include a new Division of Medical Genetics. He envisioned the new division carrying out teaching, research, and patient care related to hereditary disorders, much as other subspecialty divisions did for, e.g., cardiac or endocrine disorders. Initially, the genetic aspects of heart disease was the primary focus at the Moore Clinic (as it was renamed in 1957) and McKusick continued doing research on heart sounds until the early 1960s.
McKusick immediately instituted a postdoctoral program at the clinic, and a PhD program was later added. (Distinguished alumnae include David Rimoin, David A. Price Evans, Malcolm Ferguson-Smith, Roger Donahue, and David J. Weatherall.) The Medical Genetics Division included five sections: biochemical genetics (studying inborn errors of metabolism), cytogenetics (studying the physical structure of chromosomes), immunogenetics (studying blood group inheritance), mathematical and statistical genetics (population studies and pedigrees), and clinical genetics. Within these, the research focused on nosology (defining the multiple distinct forms of genetic diseases) and on gene mapping (tracing the chromosomal locations of inherited disease genes and their linkages to other genes.) The Moore Clinic thus was able to foster productive collaborations and to serve as a strong base for the expansion of medical genetics as a discipline. During its first several decades, its staff and fellows identified and mapped many inherited diseases, and contributed to the care of those who suffered with them. Equally important, McKusick and his colleagues helped develop educational and collaborative networks for medical genetics outside of the Moore Clinic, drawing together clinicians and researchers throughout the world.