The emergence of new genetic information provides unprecedented opportunities for practicing physicians to understand, diagnose, and treat genetic disorders, but much work needs to be done before medical genetic principles and genetic technology are fully integrated into clinical practice. Although a surfeit of information is available about many single gene disorders, our knowledge base is still limited in many areas of human genetics, including understanding of the pathogenesis of most genetic disorders. Moreover, few effective interventions exist for most genetic diseases.

Because genotype-phenotype correlations are still in their infancy, the prognostic value of most genetic tests is limited. The degree of penetrance of specific genotypic profiles varies widely. For example, many persons who are homozygous for a specific mutation will present with all of the cardinal clinical features of the disease in question, whereas others with the same mutations will not develop any signs or symptoms of the disorder during their lifetime. Still others will manifest mild symptoms. Although hypotheses abound to explain these phenomena, little information is available on the effect of other genes or the role of environmental factors that might help to explain these differences.

Practical Clinical Issues

The introduction of new molecular genetic tests raises important and necessary questions about their specificity, sensitivity, and predictive value. Before these tests are incorporated into clinical practice, substantial empirical data are needed to demonstrate the risks and benefits of obtaining positive and negative results [1]. Laboratory issues, such as accreditation, quality assurance, and the use of stringent criteria during development of a new test, must be addressed [1]. Furthermore, the complex nature of genetic disorders and the related genetic screening and diagnostic tests requires that providers become genetically literate [1, 2]. Effective communication between physician and patient (and the patient's family) about the relevant issues is time consuming. Informed consent must be obtained when predictive genetic tests are used. The ethical, legal, social, and psychological issues associated with the use of genetic information add yet another layer of complexity to discussions about the risks and benefits of testing for genetic disease. The implications of genetic disorders for family members need to be handled in a constructive and sensitive manner.

At present, most internists consider genetic testing primarily for individual patients and on a case-by-case basis. Patients who present with clinical signs or symptoms of a particular genetic disorder or those who are at risk for a genetic disorder because of a family history, findings on the physical examination, or the results of a laboratory test clearly warrant closer genetic scrutiny. Persons identified through these routes are eligible for an appropriate medical genetic diagnostic workup, including access to available genetic tests and appropriate expert counseling about the risks and benefits of undergoing those tests. Depending on the circumstances, it may be necessary to offer other family members access to these services.

Until recently, most physicians believed that medical genetics focused solely on rare or less common diseases. Such views are no longer tenable. During the past 8 years, many common disorders, such as colorectal cancer, breast cancer, and Alzheimer disease, have been successfully subjected to genetic analysis, thus opening up new possibilities for diagnosis and case management.

Expanded knowledge about the mutational basis of genetic disease also provides new opportunities for detection of disease in the public health arena. The discussion here has shifted from the provision of individual case-based genetic services to targeted population screening programs for genetic disease [3]. Such general population screening programs are designed to meet established criteria [4]. For example, population screening programs must offer opportunities to identify persons at risk for common health problems that are associated with substantial morbidity and have accepted treatment. Such programs are undertaken only when persons have access to diagnostic and treatment facilities; screening must be done with a suitable test [4].

The Case of Hemochromatosis: Screening Individual Patients and Families

The excellent series of articles in the supplement to this issue of Annals provides the reader with the background information necessary to weigh the pros and cons of pursuing population screening for HLA-linked hemochromatosis. Interest in hemochromatosis is substantial because it is a common genetic disorder associated with increased morbidity and mortality [5-8]. Because persons with hereditary hemochromatosis absorb excessive dietary iron, excessive iron overload insidiously develops in certain vulnerable tissues. If the condition is not recognized in a timely fashion, persons with hereditary hemochromatosis will develop hepatic cirrhosis, congestive heart failure, arrhythmias, diabetes mellitus, and arthritis and will have decreased life expectancy [5-8].

Hemochromatosis also became the leading candidate for population screening in part because effective and simple therapy by means of phlebotomy is readily available. If the diagnosis is made sufficiently early in the course of the disease, a therapeutic regimen can be implemented that will permit normal life expectancy and quality of life.

An effective clinical screening test for hemochromatosis is also available. This test distinguishes persons with abnormal serum iron measures from persons with normal iron values. The screening test of choice is measurement of serum transferrin saturation because it is the most sensitive for phenotypic identification. Measurement of serum ferritin levels is also used to assess iron load [9].

On this background, the use of DNA-based tests in population screening programs for hereditary hemochromatosis has recently surfaced. The discovery of a strong candidate gene for HLA-linked hereditary hemochromatosis and the 1996 identification of two distinct mutations within the HFE gene [10, 11] has prompted intense and ongoing discussion about the appropriate use of genetic studies in population screening.

However, in a recent review of the existing data, a multidisciplinary expert panel concluded that genetic testing for hereditary hemochromatosis is not recommended in population-based screening [12]. The panel primarily based this decision on the lack of data on the penetrance of the two known hemochromatosis mutations and on the uncertain predictive value of specific genotypes for future disease. The panel also concluded that more information is needed on the proportion of persons carrying specific mutations, the distribution of the various mutations in different ethnic groups, and sex- and age-related differences in expression of these mutations [12]. Panel members also believed that other, as-yet undetected mutations for hemochromatosis probably exist [12]. The presence of unknown mutations is a known confounding factor in genetic analysis. The panel emphasized the need to obtain more data on the psychological, social, and economic consequences of genetic testing for hemochromatosis before DNA testing is incorporated into large-scale screening efforts [12].

In their consensus statement, the panel cautioned that the use of DNA tests be restricted to research protocols at this time [12], with two exceptions. Panelists thought that the use of genetic tests in family-based screening could be considered [12] but only if the affected person in the family (proband) has two identified mutations. Confirmatory testing for hereditary hemochromatosis could also include genetic analysis if the proband's hemochromatosis mutations are known [12]. Offering tests in these circumstances requires expert counseling about the exact nature of the information that the test would provide.

The need for genetic expertise is particularly acute in counseling other family members. These relatives need to understand that if they are found to be homozygous for the same mutations as the proband, they may already express the gene or may be at increased risk to do so in the future. However, because the degree of penetrance in any given person is unknown, the risk for clinical expression is also unknown. It is important that all relatives of a proband who opt for testing by means of genetic analysis understand that at least some homozygous persons will not develop problematic iron overload during their lifetime.

Identification of heterozygosity also requires an explanation of carrier status and the fact that the test will identify only that specific mutation. Additional mutations, if present, may not be identified. Persons found not to be homozygous for the HFE mutations that were identified in a relative in whom hemochromatosis has been diagnosed also need to realize that their test results do not rule out the presence of other hemochromatosis genes. For all of these reasons and more, most medical geneticists would not yet recommend screening young children for hemochromatosis mutations.

Screening Populations for Hemochromatosis

Although it is unlikely that DNA-based tests will be incorporated into screening programs in the near future, the core elements for designing clinical screening programs for hereditary hemochromatosis are already in place. In fact, pilot programs have been conducted at various sites [13]. Some of these are discussed in the article by McDonnell and colleagues in the supplement to this issue of Annals [14]. The experiences gleaned from these trials provide valuable information about the problems encountered in crafting such programs. The problems include the need to establish case definitions, set appropriate threshold values for the screening test, and introduce laboratory standardization. The organizers of these programs also described and quantified problems with patient compliance, and they identified a need for physician education before such programs are developed. Concerns were also voiced about the possibility of medical and genetic discrimination. The critical need to have protocols in place for informed consent was highlighted. Screening protocols will need to be modified to deal with the incidental diagnosis of iron deficiency in the next round of screening programs. A critical clinical question that emerged from this work is the timing of treatment of a healthy asymptomatic patient who has been identified through screening as being at increased future risk for developing the clinical features of hemochromatosis.

Despite the pitfalls of population screening for hereditary hemochromatosis (including the uncertainty about the future role of genetic tests in these endeavors), interest in and support for population screening for both common genetic diseases and common diseases with a strong genetic component (the so-called multifactorial genetic disorders) will continue to grow. Many internists are now and will continue to be involved in implementing such screening programs. In addition, physicians will continue to assume responsibility for the diagnosis, treatment, and management of patients with hereditary hemochromatosis.

Genetic diseases and new molecular diagnostic techniques will continue to pose major challenges for all physicians. If genetic testing and, ultimately, new genetic information and genetic technologies are to be widely and effectively applied in treating genetic disorders, all clinicians will need to be familiar with both the clinical and genetic issues of genetic disease and be prepared to use the benefits of genetic advances in their daily practice.