Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics

Foundations

Reed E. Pyeritz,Bruce R. Korf,Wayne W. Grody

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128126851
• Edition: 7
• Topic: Medicina
• Subtopic: Genetica in medicina

For decades, Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics has served as the ultimate resource for clinicians integrating genetics into medical practice. With detailed coverage in contributions from over 250 of the world's most trusted authorities in medical genetics and a series of 11 volumes available for individual sale, the Seventh Edition of this classic reference includes the latest information on seminal topics such as prenatal diagnosis, genome and exome sequencing, public health genetics, genetic counseling, and management and treatment strategies to complete its coverage of this growing field for medical students, residents, physicians, and researchers involved in the care of patients with genetic conditions. This comprehensive yet practical resource emphasizes theory and research fundamentals related to applications of medical genetics across the full spectrum of inherited disorders and applications to medicine more broadly.

This volume, Foundations, summarizes basic theories, concepts, research areas, and the history of medical genetics, providing a contextual framework for integrating genetics into medical practice. In this new edition, clinically oriented information is supported by full-color images and expanded sections on the foundations of genetic analytics, next generation sequencing, and therapeutics.

With regular advances in genomic technologies propelling precision medicine into the clinic, Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics: Seventh Edition bridges the gap between high-level molecular genetics and practical application and serves as an invaluable clinical tool for the health professionals and researchers.

• Introduces genetic researchers, students, and health professionals to basic theories, concepts, research areas, and the history of medical genetics, offering a contextual framework for integrating genetics into medical practice
• Completely revised and up-to-date, this new edition highlights traditional approaches and new developments in the field of medical genetics, including cancer genetics, genomic technologies, genome and exome sequencing, prenatal diagnosis, public health genetics, genetic counseling, and single-cell analysis for diagnosis
• Includes color images supporting identification, concept illustration, and method processing
• Features contributions by leading international researchers and practitioners of medical genetics

1

Medicine in a Genetic and Genomic Context∗

Reed E. Pyeritz Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Abstract

The idea that all diseases are to greater or lesser degrees “genetic” is far from a new concept. The advent of genomics, which makes possible the study of the genetics of diseases of complex origin in families of patients who have affected relatives as well as in those who do not, emphasizes that genetic variation underlies the latter no less than the former. In disease, the variant gene products and the experiences of the environment with which they are incongruent account for characteristic signs and symptoms. Understanding the meaning of individuality in medicine will enable improved possibility and plausibility of prevention and treatment.

Keywords

Genetic etiology; homeostasis; pathogenetics; precision medicine

1.1. Introduction: Our History

The history of science is characterized by an exponential rate of expansion [1]. No aspect has escaped, but biology, which is relatively new, has by all accounts exploded. Naturally, these changes are reflected in new principles, new thinking, and new ways of handling new information. Among the problems created is that of making these novelties available to practitioners of science of all kinds.

Among the ways suitable to medicine are massive print volumes that contain detailed summaries of diseases, usually of one class, such as endocrine, gastroenterological, or, as in the case of Principles and Practice of Medical Genetics and Genomics (PPMGG), inherited. And of course, the pace of change requires revisions, always characterized by increases that reflect the rate of accumulation. Fission adds volumes whose pages, chapters, contributors, and diseases all do their best to obey the exponential imperative. Each chapter represents one topic more or less, an expansible topic capable of embracing new disorders with each new edition, so the number of chapters is no guide to the number of diseases. Durin the past decade, print volumes are increasingly being supplement, or even replaced, by documents available electronically. In addition to new diseases, new paths of basic science are added, a characteristic of books that mirrors progress in reductionist investigation.

But where is reductionist biology taking us? Clearly, one direction is toward fragmentation; more and more is learned about increasingly restricted fields so that even specialties bifurcate and medicine becomes ever more splintered. But despite such assaults, whatever it is we call “medicine” has at the bottom some integrity, some consistency, and common grounds that are clearly revealed in PPMGG as well as in its sister enterprise, The Metabolic and Molecular Basis of Inherited Disease (MMBID) [2]. One such common ground is genetics. And as such a striking variety of disorders of cellular structures and metabolic mechanisms engaging every organ and organ system are included in both of these books, it is easy to imagine that genetic variation is the basis of all diseases. This idea is far from new, having been suggested even in the 18th and 19th centuries, when it took the form of diathesis and idiosyncrasy [3]. Then, in this century, it appears in the shape of a continuity between clear-cut segregating monogenic diseases and varying degrees of familial aggregation of cases that suggest the outcomes of the actions of more than one gene acting in environments favorable for the onset of a disease. But now, with the advent of genomics, which makes possible the study of the genetics of diseases of complex origin in families of patients who have affected relatives, as well as in those who do not, we are learning that genetic variation underlies the latter no less than the former. So the continuity of segregating to nonsegregating familial aggregation is extended to include cases where there is neither segregation nor aggregation [4]. Perhaps we should require a disease to be shown not to be associated with any genetic variation, before saying it has no genetic basis. (refer to the chapter on The Genetics of Common Disease).

All professions undergoing rapid change and increasing specialism face the same dilemma. The generalists, who must keep up, find the density of new information daunting, even impossible, to assess and retain. So, books such as the PPMGG are intended to present this information in an orderly way and in relation to specific diseases. But the job is no sooner done than even newer information arrives to change how the various disorders are perceived and, of course, treated. Furthermore, new diseases have been described and must be included. Hence another edition must appear. And that’s not all. The various sciences that contribute to our understanding are all changing, too, providing new insights that challenge conventional thinking. Editors respond to this intense pressure by including articles that present not only new information but also new insights, new ways of thinking about groups of diseases or perhaps all, and these usually appear at the beginning, hinting strongly that the reader of any later chapter would do well to read these preliminary ones.

Perhaps focusing first on the principles of chromosomal organization, genomics, and the investigations of diseases of complex origin will assist in understanding the chapters on developmental anomalies, the origins of high blood pressure, or inborn errors. And this may happen, given the effort. But each reader who makes this synthesis for himself or herself is likely to do it in the context of some specific disorder rather than to generalize the principles to all diseases. Indeed, we lack a clearly articulated set of principles of disease as opposed to diseases. That is not to say that medicine lacks principles; the idea of the body as a machine that breaks and needs fixing is one, and the medical history, diagnosis, pathogenesis, treatment, prognosis, and prevention all have a conceptual basis, as do the basic sciences related to medicine. But disease as a concept seems to be taken for granted. However, PPMGG certainly does not suggest that a student of medicine (and we are all students throughout the length of our careers) might take profit in an account of disease as opposed to diseases, including why we have it, who is likely to be affected and how, and when in the lifetime and what forms can it take, as well as what are its constraints. That is, what are the explanatory generalizations that compose a context within which to fit all diseases?

Similarly, definitions of disease have fallen by the wayside. It is true that many such definitions have been offered; there is a sizable literature on the subject [5–8]. Perhaps today’s reluctance stems from physicians’ perception that we have not had the wherewithal for any but descriptions based on signs and symptoms rather than anything at its core. But today we are satisfied with a definition of a disease when pathogenesis is explained by reference to abnormality of some metabolic or homeostatic system, and we can describe the qualities of the proteins that compose the system. Now, if that is so, why may we not define disease as a consequence of incongruence of a metabolic or homeostatic system with conditions of life? And as all such systems are composed of proteins capable of reflecting the variations of their genetic origins, is it not appropriate to agree with Vogel and Motulsky, who, in the third edition of their book Human Genetics, proclaimed genetics as the principal “basic science for medicine” [9]?

If genetics is the basic science for medicine, it should be possible to construct a set of principles that characterize disease in a genetic context—that is, a set of generalizations shared by all diseases and framed in genetic terms. And there should be hierarchies of principles, inclusive and of increasing generality and forming a matrix embracing them all. What follows is one such matrix.

1.2. The Principles of Disease

A foundation for developing principles of disease exists in the ideas of Ernst Mayr [10]. Mayr perceived biology as divided into two areas differing in concept and method. One, functional biology, is concerned with the operation and interaction of molecules, systems, and organisms. Causes are proximate, the viewpoint is inward, and questions are commonly preceded by how; how does the organism function? The other area, Mayr calls evolutionary. It is concerned with the history of functional biology, its causes are called ultimate, and its questions are prefaced by why; why in the sense of, what is the history of organisms, what are the conditions of the past that have made it possible to ask for answers to the how questions? The two areas of biology meet, or overlap, at the level of the DNA, so that the functional deals with everything after transcription, whereas the evolutionary centers on the history of the DNA as well as, presumably, with the evolution of the conditions of the environment within which organisms have attained their current state.

Mayr did not include disease in his description of the two biologies, but disease is no less biological than the ideal state, so there should be no difficulty in applying his principles to biological abnormality. Thus, in relation to disease, the proximate causes are the products of the variant genes and the experiences of the environment with which they are incongruent. Ultimate or remote causes are first, the mechanisms of mutation and the causes of fluctuations through time of the elements of the gene pool, including selection, mating systems, founder effects, and drift, and second, the means whereby cultures and social organization evolve. In disease, the variant gene products and the experiences of the environment with which they are incongruent account for characteristic signs and symptoms, but in making available the particular proximate causes assembled by chance in particular patients, it is the remote causes that impart the stamp of individuality to the case.

So the model relates disease to causes, to the gene pool and ultimately to biological evolution, as well as to the evolution of cultures, and to individuality, the latter a consequence of the specificities of both causes. Here there are also elements for constructing a context of principles of disease, always remembering that the word context derives from the Latin word contexere, meaning “to weave.” That is, the principles must be seen to be related and interdependent so as to form a network of ideas within which to compose one’s thoughts about each specific example of each disease.

There is a further feature of Mayr’s views on biology, also crucial in its application to disease [11]. It is the state of mind in which to observe patients. In medicine, we tend to think of patients in relation to their disease, that is, as a class of people characterized by the name of the disease. This is what Mayr calls “typological thinking.” Althoug...