The Birth and Development of Genetics and Genomics
Few areas of science and medicine are seeing advances at the pace we are experiencing in the related fields of genetics and genomics. It may appear surprising to many students today, then, to learn that an appreciation of the role of genetics in medicine dates back well over a century, to the recognition by the British physician Archibald Garrod and others that Mendel's laws of inheritance could explain the recurrence of certain clinical disorders in families. During the ensuing years, with developments in cellular and molecular biology, the field of medical genetics grew from a small clinical subspecialty concerned with a few rare hereditary disorders to a recognized medical specialty whose concepts and approaches are important components of the diagnosis and management of many disorders, both common and rare.
At the beginning of the 21st century, the Human Genome Project provided a virtually complete sequence of human DNA—our genome (the suffix -ome coming from the Greek for “all” or “complete”)—which now serves as the foundation of efforts to catalogue all human genes, understand their structure and regulation, determine the extent of variation in these genes in different populations, and uncover how genetic variation contributes to disease. The human genome of any individual can now be studied in its entirety, rather than one gene at a time. These developments are making possible the field of genomic medicine, which seeks to apply a large-scale analysis of the human genome and its products, including the control of gene expression, human gene variation, and interactions between genes and the environment, to medical care.
Genetics and Genomics in Medicine
The Practice of Genetics
The medical geneticist is usually a physician who works as part of a team of health care providers, including many other physicians, nurses, and genetic counselors, to evaluate patients for possible hereditary diseases. They characterize the patient's illness through careful history taking and physical examination, assess possible modes of inheritance, arrange for diagnostic testing, develop treatment and surveillance plans, and participate in outreach to other family members at risk for the disorder.
However, genetic principles and approaches are not restricted to any one medical specialty or subspecialty; they permeate many, and perhaps all, areas of medicine. Here are just a few examples of how genetics and genomics are applied to medicine today:
• A pediatrician evaluates a child with multiple congenital malformations and orders a high-resolution genomic test for submicroscopic chromosomal deletions or duplications that are below the level of resolution of routine chromosome analysis (Case 32).
• A genetic counselor specializing in hereditary breast cancer offers education, testing, interpretation, and support to a young woman with a family history of hereditary breast and ovarian cancer (Case 7).
• An obstetrician sends a chorionic villus sample taken from a 38-year-old pregnant woman to a cytogenetics laboratory for confirmation of abnormalities in the number or structure of the fetal chromosomes, following a positive screening result from a non-invasive prenatal blood test (see Chapter 17).
• A hematologist combines family and medical history with gene testing of a young adult with deep venous thrombosis to assess the benefits and risks of initiating and maintaining anticoagulant therapy (Case 46).
• A surgeon uses gene expression array analysis of a lung tumor sample to determine prognosis and to guide therapeutic decision making (see Chapter 15).
• A pediatric oncologist tests her patients for genetic variations that can predict a good response or an adverse reaction to a chemotherapeutic agent (Case 45).
• A neurologist and genetic counselor provide APOE gene testing for Alzheimer disease susceptibility for a woman with a strong family history of the disease so she can make appropriate long-term financial plans (Case 4).
• A forensic pathologist uses databases of genetic polymorphisms in his analysis of DNA samples obtained from victims' personal items and surviving relatives to identify remains from an airline crash.
• A gastroenterologist orders genome sequence analysis for a child with a multiyear history of life-threatening and intractable inflammatory bowel disease. Sequencing reveals a mutation in a previously unsuspected gene, clarifying the clinical diagnosis and altering treatment for the patient (see Chapter 16).
• Scientists in the pharmaceutical industry sequence cancer cell DNA to identify specific changes in oncogenic signaling pathways inappropriately activated by a somatic mutation, leading to the development of specific inhibitors that reliably induce remissions of the cancers in patients (Case 10).
Categories of Genetic Disease
Virtually any disease is the result of the combined action of genes and environment, but the relative role of the genetic component may be large or small. Among disorders caused wholly or partly by genetic factors, three main types are recognized: chromosome disorders, single-gene disorders, and multifactorial disorders.
In chromosome disorders, the defect is due not to a single mistake in the genetic blueprint but to an excess or a deficiency of the genes located on entire chromosomes or chromosome segments. For example, the presence of an extra copy of one chromosome, chromosome 21, underlies a specific disorder, Down syndrome, even though no individual gene on that chromosome is abnormal. Duplication or deletion of smaller segments of chromosomes, ranging in size from only a single gene up to a few percent of a chromosome's length, can cause complex birth defects like DiGeorge syndrome or even isolated autism without any obvious physical abnormalities. As a group, chromosome disorders are common, affecting approximately 7 per 1000 liveborn infants and accounting for approximately half of all spontaneous abortions occurring in the first trimester of pregnancy. These types of disorders are discussed in Chapter 6.
Single-gene defects are caused by pathogenic mutations in individual genes. The mutation may be present on both chromosomes of a pair (one of paternal origin and one of maternal origin) or on only one chromosome of a pair (matched with a normal copy of that gene on the other copy of that chromosome). Single-gene defects often cause diseases that follow one of the classic inheritance patterns in families (autosomal recessive, autosomal dominant, or X-linked). In a few cases, the mutation is in the mitochondrial rather than in the nuclear genome. In any case, the cause is a critical error in the genetic information carried by a single gene. Single-gene disorders such as cystic fibrosis (Case 12), sickle cell anemia (Case 42), and Marfan syndrome (Case 30) usually exhibit obvious and characteristic pedigree patterns. Most such defects are rare, with a frequency that may be as high as 1 in 500 to 1000 individuals but is usually much less. Although individually rare, single-gene disorders as a group are responsible for a significant proportion of disease and death. Overall, the incidence of serious single-gene disorders in the pediatric population has been estimated to be approximately 1 per 300 liveborn infants; over an entire lifetime, the prevalence of single-gene disorders is 1 in 50. These disorders are discussed in Chapter 7.
Multifactorial disease with complex inheritance describes the majority of diseases in which there is a genetic contribution, as evidenced by increased risk for disease (compared to the general public) in identical twins or close relatives of affected individuals, and yet the family history does not fit the inheritance patterns seen typically in single-gene defects. Multifactorial diseases include congenital malformations such as Hirschsprung disease (Case 22), cleft lip and palate, and congenital heart defects, as well as many common disorders of adult life, such as Alzheimer disease (Case 4), diabetes, and coronary artery disease. There appears to be no single error in the genetic information in many of these conditions. Rather, the disease is the result of the combined impact of variant forms of many different genes; each variant may cause, protect from, or predispose to a serious defect, often in concert with or triggered by environmental factors. Estimates of the impact of multifactorial disease range from 5% in the pediatric population to more than 60% in the entire population. These disorders are the subject of Chapter 8.
Onward
During the 50-year professional life of today's professional and graduate students, extensive changes are likely to take place in the discovery, development, and use of genetic and genomic knowledge and tools in medicine. Judging from the quickening pace of discovery within only the past decade, it is virtually certain that we are just at the beginning of a revolution in integrating knowledge of genetics and the genome into public health and the practice of medicine. An introduction to the language and concepts of human and medical genetics and an appreciation of the genetic and genomic perspective on health and disease will form a framework for lifelong learning that is part of every health professional's career.
General References
Feero WG, Guttmacher AE, Collins FS. Genomic medicine—an updated primer. N Engl J Med. 2010;362:2001–2011.
ed 2. Elsevier: New York; 2012. Ginsburg G, Willard HF. Genomic and personalized medicine. vols 1 & 2.