Viewing Victor McKusick’s Legacy through the Lens of his Bibliography

Abstract

Victor McKusick’s contributions to the field of medical genetics are legendary, and include his contributions as a mentor, as creator of Mendelian Inheritance in Man (now Online Mendelian Inheritance in Man [OMIM^®]), and as a leader in the field of medical genetics. McKusick’s full bibliography includes 772 publications. Here we review the 453 papers authored by McKusick and indexed in PubMed, from his earliest paper published in the New England Journal of Medicine in 1949 to his last paper published in American Journal of Medical Genetics Part A in 2008. This review of his bibliography chronicles McKusick’s evolution from an internist and cardiologist with an interest in genetics to an esteemed leader in the growing field of medical genetics. Review of his bibliography also provides a historical perspective of the development of the discipline of medical genetics. This field came into its own during his lifetime, transitioning from the study of interesting cases and families used to codify basic medical genetics principles to an accredited medical specialty that is expected to transform healthcare. Along the way, he helped to unite the fields of medical and human genetics to focus on mapping the human genome, culminating in completion of the Human Genome Project. This review confirms the critical role played by Victor McKusick as the founding father of medical genetics.

Dr. Victor McKusick’s impact on the field of medical genetics is legendary. He is often referred to as the “father of medical genetics” and will long be remembered for his role as a mentor of faculty, fellows, residents and students (121 people were listed as genetics trainees supervised by him) (Pyeritz, 2008); as the creator and primary author for over 30 years of Mendelian Inheritance in Man (McKusick, 1966b) (now Online Mendelian Inheritance in Man [OMIM^®]); and as an esteemed leader in the field of medical genetics. Review of his bibliography provides a comprehensive summary of McKusick’s many contributions to the fields of medicine and medical genetics as well as provides insights into his evolution from an internist and cardiologist with an interest in genetics to a world-class leader in the emerging field of medical genetics. Further, review of his bibliography gives a view of the evolution of medical genetics from a subspecialty within medicine to its current role as a force that is on target to transform healthcare within the next decade (Denny & Collins, 2021).

Victor McKusick is an author on 453 papers indexed in PubMed. His earliest paper was published in the New England Journal of Medicine in 1949 (Jeghers et al., 1949), and his last paper was published in American Journal of Medical Genetics Part A in 2008 (Cathey et al., 2008). In 1971, he published 28 papers, his highest number in a year (Figure). The journal that McKusick published in most frequently was Birth Defects: Original Article Series, with 39 publications (Table 1). This journal, published by the March of Dimes Birth Defects Foundation from 1965 through 1996, summarized discussions that occurred at annual week-long conferences on the clinical delineation of birth defects initially held at Johns Hopkins from 1968–1972 (McKusick, 1971a; McKusick, 2005). McKusick later noted that these conferences “gave academic respectability to the disciplines of syndromology and dysmorphology. No longer could these fields be considered mere postage stamp collecting.” (McKusick, 2006). Other journals in which McKusick frequently published (Table 1) include Bulletin of the Johns Hopkins Hospital (later known as Johns Hopkins Medical Journal – publication of this journal was discontinued in 1982), American Journal of Human Genetics (the official journal of the American Society of Human Genetics), Journal of the American Medical Association, New England Journal of Medicine, Medicine, Journal of Chronic Disease, Lancet, American Journal of Medicine, Journal of Medical Genetics, and American Journal of Medical Genetics (including Part A and Part C).

Figure:

Publications authored by Dr. Victor McKusick by Year, according to PubMed

Table 1.

Journals in which Dr. Victor McKusick most frequently published according to PubMed

Journal	# of publications
Birth Defects Original Article Series	39
Bulletin of the Johns Hopkins Hospital/Johns Hopkins Medical Journal	29
American Journal of Human Genetics	26
Journal of the American Medical Association (JAMA)	22
New England Journal of Medicine	21
Medicine (Baltimore)	14
Lancet	11
American Journal of Medicine	10
Journal of Medical Genetics	10
American Journal of Medical Genetics (including Parts A and C)	10

April 2021 search results from PubMed, Scopus, and Web of Science show McKusick was first author on 49% of his papers and last (senior) author on 30%. According to Scopus, he had over 950 coauthors. His most frequent coauthors on papers indexed in PubMed were David Rimoin (19 papers), Thomas Merimee (16 papers), Reed Pyeritz (11 papers), David Rabinowitz (11 papers), Wilma Bias (10 papers), Harold Cross (11 papers), George Martin (10 papers), J. Larmont Murdoch (9 papers), and George Webb (9 papers).

Of note, the first paper submitted by McKusick when he was a medical student, coauthored with his brother Robert, was on the inheritance of coat color in cattle. This paper, submitted to the Journal of Heredity, was never published; in fact, the submission was never acknowledged by the journal (Collins, 2008).

A review of McKusick’s papers show an evolution from his early work in internal medicine and cardiology toward a focus on medical genetics. Interestingly, however, his first paper indexed in PubMed, published in 1949 in the New England Journal of Medicine (Jeghers et al., 1949), was on a genetic condition. The paper, titled “Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance”, was a description of ten patients with what is now known as Peutz-Jeghers syndrome (OMIM# 175200), an autosomal dominant condition characterized by melanin pigmentation of the oral mucosa, lips and digits associated with intestinal polyposis. His coauthors were Drs. Harold Jeghers and Kermit Katz from Boston City Hospital/Boston University School of Medicine, and Georgetown University School of Medicine, respectively. McKusick noted in a later paper (McKusick, 2006) that he saw his first patient with Peutz-Jeghers syndrome during the final month of his Osler internship at Johns Hopkins and commented that this patient was “the most important influence directing me into medical genetics”. In the next year, he saw four more patients (three from the same family) at Johns Hopkins who also had what he referred to as the “polyps-and-spots syndrome” (McKusick, 2006). These cases, combined with five cases seen by Harold Jeghers, were reported in a paper that has been cited over 500 times (Jeghers et al., 1949) (Table 2). McKusick later noted that the principle of genetic pleiotropism (that a single gene could cause multiple effects – both intestinal polyps and the melanin hyperpigmented lesions) that he recognized in Peutz-Jeghers syndrome led him later, as a cardiologist, to recognize the pleiotropic effects of a single gene (i.e., eye, skeletal, and aortic features) in patients with Marfan syndrome (OMIM# 154700) (McKusick, 2005).

Table 2.

Most Frequently Cited Papers authored by Dr. Victor McKusick according to Web of Science^*

Title	Reference	Journal	Year of publication	DOI	# of citations
The sequence of the human genome	(Venter et al., 2001)	Science	2001	10.1126/science.1058040	8746
Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders	(Hamosh et al., 2005)	Nucleic Acids Res	2005	doi.org/10.1093/nar/gki033	1503
Genetic Control of Isoniazid Metabolism in Man	(Evans et al., 1960)	Br Med J	1960	10.1136/bmj.2.5197.485	690
Current Concepts – Marfan Syndrome – Diagnosis and Management	(Pyeritz & McKusick, 1979)	N Engl J Med	1979	10.1056/NEJM197904053001406	654
Life Expectancy and Causes of Death in Marfan Syndrome	(Murdoch et al., 1972a)	N Engl J Med	1972	10.1056/NEJM197204132861502	575
Generalized Intestinal Polyposis and Melanin Spots of the Oral Mucosa, Lips and Digits – A Syndrome of Diagnostic Significance	(Jeghers et al., 1949)	N Engl J Med	1949	10.1056/NEJM194912222412501	509
International Nosology of Heritable Disorders of Connective-Tissue, Berlin, 1986	(Beighton et al., 1988)	Am J Med Genet	1988	10.1002/ajmg.1320290316	492
The Cardiovascular Aspects of Marfan’s Syndrome: A Heritable Disorder of Connective Tissue	(McKusick, 1955a)	Circulation	1955	10.1161/01.CIR.11.3.321	453
Implications of the Human Genome Project for Medical Science	(Collins & McKusick, 2001)	JAMA	2001	10.1001/jama.285.5.540	438
Patients with Ehlers-Danlos Syndrome Type IV Lack Type-III Collagen	(Pope et al., 1975)	Proc Natl Acad Sci USA	1975	10.1073/pnas.72.4.1314	408

^*As of April 21, 2021

A survey of McKusick’s PubMed-indexed publications in five-year increments illustrates how his papers defined the field of medical genetics and highlighted the path to completion of the Human Genome Project.

1950–1954 (23 papers):

During this time period, McKusick’s work focused on cardiology and internal medicine, with papers on ventricular fibrillation (Southworth et al., 1950a; Southworth et al., 1950b), constrictive pericarditis (McKusick, 1952a; McKusick, 1952b; Scarborough et al., 1952), aortic arch syndromes (Ross & McKusick, 1953), as well as Bacteroides infections (Fisher & McKusick, 1952; Fisher & McKusick, 1953) and frequently used medications (e.g., theophylline) (Truitt et al., 1950). McKusick also demonstrated a keen interest in the history of medicine, with a paper on Bernhard Bang (Williams & McKusick, 1954), a Danish veterinarian who discovered Brucella abortus, the causative agent of contagious abortion in cattle and of brucellosis in humans. He also published a paper summarizing the minutes of the Johns Hopkins Medical History Club (McKusick, 1953), and a paper on the clinical observations of Jonathan Hutchinson, the first physician to describe the signs of congenital syphilis, including the notched incisor teeth (Hutchinson teeth) seen in the condition (McKusick, 1952c). As noted by McKusick in a later article (McKusick, 2005), this paper was written when he was a senior assistant resident on the Osler Service at Johns Hopkins where he had access to the Hutchinson collection. This collection was acquired with the assistance of Sir William Osler and was stored in eight crates in the Welch Medical Library. This paper was the first of four published by McKusick on Hutchinson’s accomplishments.

1955–1959 (42 papers):

In a later paper, McKusick referred to this period as a time of “phasing down cardiology and ramping up genetics” (McKusick, 2006). During this time, McKusick continued to publish papers on diseases of the heart (e.g., disease of the pericardium including constrictive pericarditis) (McKusick & Harvey, 1955; McKusick et al., 1955a) and heart sounds (e.g., spectral phonocardiography and musical murmurs) (McKusick, 1959; McKusick et al., 1955b). Likewise, his interest in the history of medicine also continued with several papers published in the Bulletin of the History of Medicine (McKusick, 1955e; McKusick, 1958; McKusick et al., 1957; McKusick & Wiskind, 1959).

A clear interest in genetic disorders soon became apparent. In 1955, he published his first of 25 papers on Marfan syndrome, bringing together his expertise as a cardiologist and emerging interest in genetics by focusing on the cardiovascular aspects of the autosomal dominant condition (McKusick, 1955a). During this time period, he published a series of papers on heritable disorders of connective tissue, including Marfan syndrome, Ehlers-Danlos syndrome (OMIM# 130000), osteogenesis imperfecta (OMIM# 166200), and pseudoxanthoma elasticum (OMIM# 264800) in the Journal of Chronic Disease (McKusick, 1955b; McKusick, 1955c; McKusick, 1955d; McKusick, 1956b; McKusick, 1956c; McKusick, 1956d; McKusick, 1956e; McKusick, 1956f). These articles culminated in the publication in 1956 of the first of four editions of his book Heritable Disorders of Connective Tissue (McKusick, 1956a). In addition, he published a report, his first of 25 papers in the American Journal of Human Genetics (McKusick, 1955f), of a consanguineous family in which both primordial dwarfism (OMIM# 262400) and ectopia lentis (OMIM# 225100) were inherited as separate conditions. He also summarized a symposium on inborn errors of metabolism as well as reported changes in fingernails in two patients with Wilson disease (OMIM# 277900) (Bearn & McKusick, 1958; McKusick, 1957).

1960–1964 (45 papers):

In 1960, McKusick published a paper in the Journal of Chronic Disease entitled “Medical Genetics, 1959”, which summarized key events that had occurred in 1959 in the burgeoning field (McKusick, 1960). Similar synopses were published in 1963 and 1964 in the same journal (McKusick, 1963; McKusick, 1964a). McKusick continued to play a role in updating physicians about advances in the field of medical genetics, with papers in Hospital Practice in 1976 and 1985 (McKusick, 1976; McKusick, 1985) and in the Journal of the American Medical Association in 1989, 1990, and 1993 (Caskey & McKusick, 1990; McKusick, 1989a; McKusick, 1993b). In 1961, a paper coauthored by John Fuller was published on the first short course in medical genetics, which was held in the summer of 1960 as a joint venture between Johns Hopkins and the Roscoe B. Jackson Memorial Laboratory (Fuller & McKusick, 1961). This course, now named the McKusick Short Course, will be held for the 62^nd year in 2021. During the early 1960s, he occasionally published on topics related to internal medicine (e.g., epidemiologic investigations of sarcoidosis) and cardiology (e.g., how to determine if a systolic murmur is “innocent”) (Buck & McKusick, 1961; Humphries & McKusick, 1962), but most publications at this time focused on genetics. He published several articles on X-linked conditions including colorblindness (OMIM# 303800), glucose-6-phosphate dehydrogenase deficiency (OMIM# 305900), and an X-linked form of spastic paraplegia (OMIM# 312920) (Johnston & McKusick, 1962; Porter et al., 1962). In 1964, he wrote a book entitled On the X Chromosome of Man (McKusick, 1964b). This catalog of X-linked traits served as a precursor to McKusick’s most recognized contribution, Mendelian Inheritance in Man (McKusick, 1966b).

Towards the end of this time period, McKusick began to write papers about his work with the Old Order Amish community. His first four of over 25 papers on genetic conditions in the Amish were published in 1964 (McKusick et al., 1964b; McKusick et al., 1964c; McKusick et al., 1964d; McKusick et al., 1964e). In a later paper, McKusick noted that his medical genetics interest in the Amish was initially piqued by an article about a physician who cared for Amish patients in Lancaster County, Pennsylvania, in which a comment was made that achondroplasia (OMIM# 100800), a known autosomal dominant condition, was particularly frequent among the Amish (Francomano et al., 2003). McKusick’s skepticism regarding this statement led him to study dwarfism in the Amish community, resulting in the discovery that two autosomal recessive conditions — Ellis-van Creveld syndrome (OMIM# 225500), first reported in 1940 (McKusick et al., 1964b), and a newly recognized condition called cartilage-hair hypoplasia (later known as metaphyseal chondrodysplasia, McKusick type) (OMIM# 250250) (McKusick et al., 1965) —were the cause of the high frequency of dwarfism in the Amish community. Also published during this time was a report of a new autosomal recessive condition, later known as McKusick-Kaufman syndrome (OMIM# 236700), characterized by hydrometrocolpos, polydactyly, and less often heart or gastrointestinal malformations (McKusick et al., 1964a).

1965–1969 (70 papers):

In 1965, McKusick published two papers on homocystinuria (OMIM# 236200), noting its clinical similarities to Marfan syndrome (Schimke et al., 1965a; Schimke et al., 1965b). He also published a paper on the genetic mucopolysaccharidoses (McKusick, 1965), following up on a paper he had published in 1956 on Hurler syndrome (OMIM# 607014) as a heritable disorder of connective tissue (McKusick, 1956e). Through the years, McKusick’s interest in disorders of polysaccharide and lipid storage was demonstrated with at least 20 publications on these conditions. Several papers on the genetic aspects of endocrinology were also published during this time (Rimoin et al., 1968), including a paper published in Scientific American by McKusick and David Rimoin on growth hormone deficiency (OMIM# 613038) as the proposed cause of short stature in General Tom Thumb, who had worked as a performer under circus owner P.T. Barnum (McKusick & Rimoin, 1967).

Also during this time period, papers were published that foreshadowed areas of major interest for McKusick. These included papers on “lumpers and splitters” in the nosology of genetic disease (McKusick, 1969), on linkage and mapping (Schleutermann et al., 1969), and on the use of computers in research in human genetics including using computers to aid in linkage analysis, quantitative estimate of inbreeding, and genetic nosology (McKusick, 1966a). A key paper during this time was a paper published in 1968 in the Proceedings of the National Academy of Sciences describing the first assignment of a specific gene, the Duffy blood group locus, to a specific autosome (chromosome 1) (Donahue et al., 1968). In 1966, the first edition of Mendelian Inheritance in Man, A Catalog of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes (MIM) was published (McKusick, 1966b). It cataloged a total of 1,487 genetic phenotypes and was printed from files stored on computer tape. By the end of this decade, McKusick published the second edition of Mendelian Inheritance in Man (McKusick, 1968), which included entries for 1,545 phenotypes.

1970–1974 (89 papers):

One of the first papers published in this five-year period was a 46 page review of human genetics in which McKusick provided a comprehensive update on advances in the fields of cytogenetics, biochemical genetics, immunogenetics, statistical and population genetics, and clinical genetics, that cited 433 references (McKusick, 1970). Included in this paper was a discussion of prenatal diagnosis of Down syndrome and other genetic conditions, a service that had become available in the late 1960s; McKusick noted that “questions of moral, ethical, legal, and political nature are raised” by recent advances in the field. Other papers published during this time period included six papers on Marfan syndrome, including papers on life expectancy and causes of death (Murdoch et al., 1972a), parental age effects on the occurrence of new mutations (Murdoch et al., 1972b), and a description of transverse striae distensae in the lumbar area in patients with the condition (McKusick, 1971c). His interest in Ehlers-Danlos syndrome also continued during this time period with four papers on the topic, including one describing the defects in conversion of procollagen to collagen in Ehlers-Danlos syndrome type VIIB published in Science (Lichtenstein et al., 1973).

During this time period, McKusick’s interest in skeletal dysplasias continued, with publication of several papers, including ones on achondroplasia (Murdoch et al., 1970), hypochondroplasia (OMIM# 146000) (Walker et al., 1971), pseudoachondroplasia (OMIM# 177170) (Kopits et al., 1974), Kniest syndrome (OMIM# 156550) (Siggers et al., 1974), and diastrophic dysplasia (OMIM# 222600) (Walker et al., 1972), as well as a paper on the obstetric and gynecologic considerations related to skeletal dysplasias (Tyson et al., 1970). Following a meeting of international experts in radiology, orthopedics, pediatrics, and genetics in Paris, McKusick and Charles Scott published a paper on the international nomenclature for skeletal dysplasias (McKusick & Scott, 1971). Nomenclature, nosology, and classification of genetic disease continued to be longstanding areas of interest.

In 1973, McKusick wrote a paper that introduced the concept of allelic series, now familiar to geneticists, in which clinically disparate phenotypes are shown to be allelic disorders; this was in contrast to the “one gene, one disorder” concept that was prevalent at the time (McKusick, 1973). McKusick also published another paper in Scientific American, this one on “The mapping of human chromosomes”, in which he noted that detailed mapping would provide “incalculable benefits”, including the possibility of early, even prenatal, diagnosis of genetic disease (McKusick, 1971b). McKusick then noted another motivation for disease mapping, “…for some of us in human genetics it is sufficient motivation that the mapping of the chromosomes, like the ascent of Mount Everest, is there to be accomplished. We find it an exciting enterprise because of its difficulty and its challenge to ingenuity.” (McKusick, 1971b).

1975–1979 (44 papers):

McKusick’s interests in Marfan syndrome continued, with seven papers published on the topic during this time period. These included papers on treatment with propranolol to prevent aortic dissection (Ose & McKusick, 1977) and with estrogen for treatment of tall stature in girls (Skovby & McKusick, 1977) with Marfan syndrome. Four papers on Ehlers-Danlos syndrome were published from 1975–1979, including a paper showing lack of type III collagen in Ehlers-Danlos syndrome type IV (OMIM# 130050) (Pope et al., 1975), now known as vascular EDS. Also during this time, a monograph on hand malformations summarizing the work of Samia Temtamy, who conducted her PhD thesis at Johns Hopkins under the direction of McKusick, was published (Temtamy & McKusick, 1978).

In 1977, McKusick received the prestigious William Allen Memorial Award from the American Society of Human Genetics at their annual meeting (awarded on his 56^th birthday), and the American Journal of Human Genetics published a summary of his acceptance lecture (McKusick, 1978). In this lecture, he discussed three primary areas of interest in his career: heritable disorders of connective tissue, gene mapping of the X and other human chromosomes, and genetics of diseases in the Amish population. In the presentation, he brought these topics together under a title of “Genetic Nosology: Three Approaches”, with genetic nosology defined in the paper as delineation of genetic diseases. At the end of the paper, he noted that the progress in genetic nosology and in gene delineation was reflected by the number of “reasonably established loci” included in Mendelian Inheritance in Man, then up to over 1300, of which 240 were assigned to a specific chromosome.

1980–1984 (32 papers):

By 1980, five International Human Gene Mapping Workshops had been held and interest was building to map the human genome, with McKusick leading the charge. He published several papers that discussed gene mapping (McKusick, 1980; McKusick, 1981a; McKusick, 1981b; McKusick, 1981c; McKusick, 1982a; McKusick, 1984), including several reports of a committee that focused on unassigned linkage groups (McKusick & Conneally, 1984). In addition, McKusick’s interest in cardiac manifestations of genetic disease continued. He published papers on cardiovascular risk in heterozygotes for homocystinuria (Mudd et al., 1981; Mudd et al., 1982), a paper on genetics and cardiovascular disease (McKusick, 1982b), and papers on cardiovascular findings of Marfan syndrome (Come et al., 1983; Pyeritz & McKusick, 1981). One of the papers on Marfan syndrome discussed surgical management of patients with Marfan syndrome and ascending aorta dilatation, and was written in collaboration with Vincent Gott (McDonald et al., 1981), a cardiovascular surgeon at Hopkins, with whom McKusick published seven papers. In 1983, he published the sixth edition of Mendelian Inheritance in Man (McKusick, 1983), which, for the first time, included some human genes that had been cloned and fully sequenced among its 3,368 entries.

1985–1989 (32 papers):

As McKusick’s passion for mapping the human genome grew, 12 of 32 papers published in these five years used the term “map” or “mapping” in the title. These included a 4-part series of articles entitled “The Morbid Anatomy of the Human Genome: A Review of Gene Mapping in Clinical Medicine” (McKusick, 1986a; McKusick, 1987a; McKusick, 1987b; McKusick, 1988). This treatise provided support for the 1988 National Research Council’s Report of the Committee on Mapping and Sequencing the Human Genome that was used to establish the Human Genome Project (National Research Council, 1988). McKusick summarized the importance of this report and that of the Office of Technology Assessment in a special article published in the New England Journal of Medicine in 1989 (McKusick, 1989c). At this time, McKusick was a member of the Committee on Mapping and Sequencing the Human Genome of the National Research Council of the National Academy of Sciences and president of Human Genome Organization (HUGO), an international coordinating agency for global mapping and sequencing efforts. Also in 1989, McKusick published a paper on HUGO, summarizing its history, purposes, and membership (McKusick, 1989b).

During this time period, McKusick’s interest in nosology/nomenclature, heritable disorders of connective tissue, and skeletal dysplasias continued (Beighton et al., 1988; Hall et al., 1987; Horton et al., 1988; McKusick, 1986b; Shows et al., 1987). In one of these papers, published with Judy Hall, a former trainee, a new concept of gonadal mosaicism was introduced to explain a family in which two siblings were affected with pseudoachondroplasia, one of whom had an affected child (Hall et al., 1987). Three papers on inbreeding and pre-reproductive mortality in the Old Order Amish, in collaboration with Muin Khoury, were published in 1987 (Khoury et al., 1987a; Khoury et al., 1987b; Khoury et al., 1987c).

1990–1994 (30 papers):

In a paper published in JAMA in 1993, McKusick provided a 40-year perspective on the evolution of medical genetics from a basic science into a medical specialty. The first sentence acknowledges a major milestone for the specialty of medical genetics: “Within the last year, medical genetics has been fully recognized as a bona fide clinical specialty”. This paper was written to acknowledge the acceptance of the American Board of Medical Genetics as the 24^th member of the American Board of Medical Specialties, with the American College of Medical Genetics established in parallel to the colleges of other specialties (McKusick, 1993b).

In the early 1990s, McKusick’s continuing interest in gene mapping was apparent through his growing interest in the Human Genome Project, which had been launched in 1991 (McKusick, 1991a; McKusick, 1991b; McKusick, 1993a). In a paper initially presented as the Presidential Address at the Eighth International Congress of Human Genetics held in 1991 (McKusick, 1992), McKusick summarized key accomplishments since the first international congress held 35 years earlier and then focused on the future of human genetics. He referred to the debate over the Human Genome Project and commented that “rarely, if ever, has the future of a scientific field and its implications for society been given such wide and intense attention.” He foresaw the concept of “reverse genetics”, moving from DNA to phenotype, common in the field today. He also correctly predicted that the Human Genome Project would initially widen the gap between diseases we can diagnose and those we know how to treat and noted that the increased availability of genetic testing could lead to pressure on couples to make choices regarding reproduction. He ended with emphasizing his impressions of contributing to the field:

“As human geneticists we are privileged to work in a scientifically important field and a field of intellectual challenge… To have combined with this intellectual and anthropocentric fascination the opportunity to contribute to human welfare and to be of service to families and individuals through medical genetics and clinical genetics … is a privilege. The privilege carries with it responsibilities…”

1995–1999 (20 papers):

In 1997, McKusick received the prestigious Albert Lasker Award for Special Achievement in Medical Science and in acknowledgment of the award, was invited to publish a commentary in Nature Medicine (McKusick, 1997). This commentary showed strong evidence of McKusick’s humility; the first two sentences of the paper stated: “This is a personal account of progress in medical genetics over the past half-century. It might be subtitled ‘The confessions of an opportunist, chauvinist, and dilettante’”. He then detailed how opportunism and serendipity played important roles in his career; how he pled mea culpa to the crimes of chauvinism (defined as exaggerated or aggressive patriotism) with his uninterrupted over 50-year tenure at Johns Hopkins; and how he confessed dilettantism for his studies ranging from the physics of cardiovascular sound, gene mapping, gene dynamics in founder populations, and delineation of genetic disorders.

In 1996, McKusick published a paper summarizing the status of surgery for the cardiovascular manifestations of Marfan syndrome, including information on 212 patients that had undergone aortic root surgery (Gott et al., 1996). This paper noted low 30-day mortality after aortic root replacement, with excellent long-term results, and included a discussion of the advances in understanding the genetics of Marfan syndrome, with identification of the causative gene FBN1 (OMIM# 134797) (Dietz et al., 1991).

Evidence of McKusick’s continued interest in nomenclature was apparent. In 1996, he published a paper emphasizing the importance of using terminology about mutations that could be universally understood (Beutler et al., 1996). In 1998, McKusick published a paper in Science that described the Human Genome Organization (HUGO) Mutation Database Initiative begun in 1994 to bring together communities interested in cataloging genetic mutations (Cotton et al., 1998). Also in this year, McKusick published a paper on challenges to the naming of genetic disorders, including a discussion of the pros and cons of using eponyms, and an argument to eliminate the possessive (e.g., to use Marfan syndrome, not Marfan’s syndrome) (McKusick, 1998b). In 1998, McKusick published the 12^th and last edition of Mendelian Inheritance in Man (McKusick, 1998a) before the resource was moved online. It contained 8,587 entries describing genes and phenotypes organized in autosomal, X-linked, Y-linked and mitochondrial catalogs.

2000–2004 (17 papers):

In March of 2000, McKusick published a memoir of A. McGehee Harvey following his death in 1998 (McKusick, 2000b). Harvey was McKusick’s predecessor as the William Osler Professor of Medicine and physician-in-chief of the Johns Hopkins Hospital and key mentor, and the two had shared an avid interest in the history of medicine. In that memoir, McKusick acknowledges Harvey’s role in institutionalizing a program in medical genetics at Hopkins by inviting McKusick to take on the directorship of the Moore clinic in 1957 (McKusick, 2000b). In May of 2000, Stylianos Antonarakis and McKusick published a paper announcing that OMIM had reached 1,000 gene entries with at least one allelic variant recognized as the cause of or associated with a human phenotype (Antonarakis & McKusick, 2000). Less than a year later, report of sequencing of the human genome by a privately funded entity was published in the February 16, 2001 issue of Science (Venter et al., 2001). The same week, a report of the publicly funded human genome sequencing effort was published in Nature (Lander et al., 2001). McKusick, an early proponent of the Human Genome Project (McKusick, 1971b; McKusick, 1991a), was an author on the paper by Venter et al. (his most frequently cited paper with more than 8000 citations) (Table 2) (Venter et al., 2001). Accompanying the paper in Science was a viewpoint (Peltonen & McKusick, 2001) that put the monumental accomplishment of the Human Genome Project into context: “Reaping the fruits of the human genome sequencing project through alleviating the suffering of patients will only be possible if available genetic information is combined with the skilled professionalism of health care workers and ethically solid standards.” The week before the publication of the two human genome sequencing papers, JAMA published a paper by Francis Collins and McKusick that discussed the profound implications of the Human Genome Project that were anticipated for medical science, noting that “virtually every human illness has a hereditary component” (Collins & McKusick, 2001). The authors identified key research opportunities, including development of safe and effective gene-transfer vectors to allow gene therapy and exploration of the ethical, legal, and social implications of genetics research. They also emphasized the need for improved understanding of genetics by clinicians and for federal legislation to prohibit the use of genetic information to discriminate against individuals in the workplace and in health insurance acquisition. Later in 2001, McKusick published a special communication in JAMA (McKusick, 2001) that compared the understanding of the human genome as having a “comparably strong and pervasive influence on all of medicine” to the book on human anatomy de corporis humani Fabrica (the fabric of the human body) published by Vesalius in 1543. McKusick emphasized that understanding genomic anatomy allows for improved diagnosis and treatment, but has a potential for misuse and misunderstanding. He emphasized again the importance of education, not only of health professionals, but of the general public.

In March of 2000, the gene for Ellis-van Creveld syndrome was identified (Ruiz-Perez et al., 2000), and in the same issue of Nature Genetics, McKusick published a paper acknowledging the many contributions of the Amish community to the improved understanding of genetic disorders (McKusick, 2000a). In this time period, a paper was published showing that cartilage-hair hypoplasia (also known as metaphyseal chondrodysplasia, McKusick type) in Amish patients (McKusick et al., 1965) was caused by a missense mutation, (70A→G), in the RMRP gene (OMIM# 157660); the same mutation that causes the disease among Finnish cases (Ridanpaa et al., 2003).

2005–2008 (7 papers):

The papers in this final phase of McKusick’s writings again reveal his appreciation for the history of medicine. He published a paper describing the clinical legacy of Jonathan Hutchinson, including two genetic syndromes that had been initially described by Hutchinson – Hutchinson-Gilford progeria syndrome (OMIM# 176670) and Peutz-Jeghers syndrome; McKusick noted that both of these conditions had recently been elucidated at the molecular level (McKusick, 2005). In the paper, initially provided as the Gordon Wilson lecture at the American Clinical and Climatological Association, McKusick used a discussion of Hutchinson’s legacy as a starting point to review his own perspective of how the description and delineation of genetic conditions proceed through stages: initial description, refinement of phenotype, defining of the Mendelian genetics, and discovery of the molecular defect at the DNA level (McKusick, 2005). In 2006, McKusick published a paper entitled “A 60-Year Tale of Spots, Maps, and Genes”, in which he detailed the origins of his interest in medicine (stemming from a 10 week stay at Massachusetts General Hospital for treatment of a severe infection at age 15 years) and his introduction to Johns Hopkins, the only medical school to which he applied and the institution where he spent his entire career. This paper discussed his career trajectory from cardiologist to medical geneticist, the fellows who he trained in the Moore clinic at Johns Hopkins, the Bar Harbor course, and his work on genetic nosology, gene mapping, Human Genome Project, and OMIM (McKusick, 2006).

The succession of Mendelian Inheritance in Man, OMIM, is one of McKusick’s most enduring legacies. He published two papers about OMIM, including one of McKusick’s most frequently cited papers, with over 1500 citations (Table 2) (Hamosh et al., 2005; McKusick, 2007). His last paper indexed in PubMed, published in the American Journal of Medical Genetics Part A in February of 2008, just a few months before his death in July, focused on updating the nomenclature of mucolipidoses II and III to incorporate understanding of the clinical, biochemical and molecular heterogeneity of these conditions (Cathey et al., 2008).

A review of McKusick’s 453 papers from 1949 to 2008 illustrate his curiosity, first in the fields of internal medicine and cardiology and then increasingly in the emergent field of medical genetics, and his strong interest in sharing new discoveries with others in the field. In the paper summarizing his 60-year career in medicine (McKusick, 2006), McKusick describes himself as “mainly an autodidact in genetics” (defined as a self-taught person). Through McKusick’s career, including his papers published in the medical literature, he has served as a primary teacher of medical genetics principles to geneticists and non-geneticists. He was an educator who trained and mentored numerous faculty, fellows, residents, students — some of whom he later continued to collaborate with on research efforts — throughout his long and illustrious career at Johns Hopkins. He also was an innovator with a passion for mapping the human genome and a vision for the future that we are facing now; one in which, while we are reaping the benefits of the Human Genome Project, we must also address the ethical, legal, and social challenges. Review of McKusick’s papers show not only the evolution of his academic interests, but the progression of the field of medical genetics from its initial focus on description and refinement of phenotypes to understanding the genetics associated with those phenotypes and their molecular defect at the DNA sequence level. As noted by Francis Collins, now Director of the National Institutes of Health, at the time of McKusick’s death, “It is the rare scientist who is universally recognized as the founder of a field. Even rarer is the one who witnesses his vision evolve from a solitary pursuit into a major discipline. But such was the life of the father of medical genetics, Victor Almon McKusick…” (Collins, 2008). Given his longstanding interest in the history of medicine, it is fitting that Victor McKusick’s legacy be added to the annals of medical history for his role as the “father of medical genetics”.