The goals of genomic medicine are to provide early detection of genetic predisposition, and to offer individualized treatment. Increasingly, genomic medicine may address common conditions known to have significant genetic components, such as hypertension, obesity, diabetes, cancer, and affective disorders. Early treatment could then be used to prevent or ameliorate some diseases, while prenatal counseling would be appropriate for diseases that are lethal, severely disabling, or cannot be treated. To optimize identification of genetic diseases and risk factors, physicians must synergistically use information about the patient's signs and symptoms, his or her family medical history, and knowledge of the genetic etiology of disease.
Knowledge of the patient's family history can play an important role in the initial detection of genetic diseases. Ideally, such histories include information about which genetic diseases have occurred in the patient, as well as in their parents, siblings, children and other relatives. From these histories risk factors can be identified to determine more accurate estimates of recurrence and predisposition.
Because of the rapid rate at which genetic bases of diseases are being discovered, there is no printed reference that can provide current information about all the clinical and laboratory findings consistent with genetic disease, or which laboratories perform specific genetic tests. Electronic databases are becoming an important source for this information because they are easy to update and can be searched interactively. For example, imagine that you are asked to see a 16-year-old girl with the following characteristics: height greater than 95th percentile, dislocated lens, pectus excavatum, and joint hypermobility. Her father died of a ruptured aortic aneurysm at age 42 years. To generate a differential diagnosis you perform a search of the Online Mendelian Inheritance in Man (OMIM) database1 which contains information on more than 12,800 genes or genetic disorders. When you search for entries containing the 5 search terms terms, "tall stature," "dislocated lens," "pectus excavatum," "joint hypermobility," the database returns only 2 OMIM entries. The first states that fibrillin mutations are the major cause of Marfan syndrome (MFS). The second states that MFS is an autosomal dominant disorder, and includes a synopsis of associated physical findings, a "Clinical Features" section, and information on the diagnosis and management of MFS. Importantly, this entry alerts you to the risk of aortic root dilation and the efficacy of β-blockers in treating this complication.
More detailed information on the signs, symptoms, diagnosis and treatment of MFS and other genetic disorders can be found in the GeneClinics database.2 This also contains the addresses, telephone, and fax numbers of several laboratories that provide molecular testing for MFS in the GeneTests database.3 This database also provides contact information for genetic clinics throughout the United States. Finally, you can find information on insurance issues and support groups for patients and their families at the Genetic Alliance web site.4 Using these databases, you have generated a working diagnosis (MFS), obtained information about its pathogenesis, mode of inheritance, diagnostic criteria and treatment, found laboratories that can provide testing, and identified support and information sources for affected individuals and families.
Further improvement of genetic diagnostic methods and treatments will require that patients and their families participate in research efforts. Such studies can utilize linkage analysis, allele sharing, or association methods to identify genes that predispose to, or provide resistance to genetic diseases. Linkage analysis determines if selected genes co-segregate with a disease. They require DNA samples from patients and members of their families. Allele sharing studies determine if selected genes are found more often in siblings who share a disease, and thus predispose those with the gene to the disease. These studies only require DNA from affected siblings. Association studies determine whether selected mutations, which may predispose to or protect against disease, occur more frequently in affected patients or a control group. Association studies require DNA from affected but unrelated patients, and from control subjects from the same population.
Elucidating and managing the immense complexity of human genetic diseases is critical to the clinical application of genetic information. Taking a careful family history and using centralized databases on the Internet are powerful and straightforward ways to identify genetic diseases. As these databases grow they will also provide more comprehensive access to treatments, specialized laboratory tests, and educational materials for patients and their families. Physicians should also help patients and their families become more aware of their own risks for genetic diseases and the potential to participate in research to discover better prevention and treatment for these diseases.
Phillips III JA. Genomic Medicine: Managing the Complexity. JAMA. 2001;286(13):1639. doi:10.1001/jama.286.13.1639-JMS1003-6-1