Clinical screening lies at the heart of preventive medicine, since identification of a disease in its earliest form offers an opportunity to intervene and disrupt its expected deleterious course. In cardiovascular medicine, clinical screening is most effective in diseases such as hypercholesterolemia, where the disease in its earliest form may not have symptoms or signs but can be readily diagnosed with an inexpensive, non-invasive test. Other aspects of a disease like hypercholesterolemia also make a systematic screening program successful: it is relatively common, it has serious consequences such as myocardial infarction, and it is treatable, with the likelihood of adverse sequelae being reduced significantly by treatment. These and other criteria are used by groups, such as the US Preventive Task Force, to develop recommendations for screening programs (http://www.ahrq.gov/clinic/USpstfix.htm).
Genetic screening is a form of screening used for diseases with a significant heritable component. It involves searching for a one or more DNA variants in individuals believed to be at risk for a disease, where the DNA variant is believed to contribute to disease incidence or progression. Prior to comparing genetic and clinical screening, it would be helpful to review some aspects of the genetic basis of disease.
Genetic diseases lie along a continuum ranging from Mendelian disorders to complex diseases, which arise from the interaction of a number of genetic and environmental factors. Mendelian disorders typically arise from a mutation in a single gene and have a sufficiently dramatic effect that those who inherit the genetic mutation typically inherit the disease. The concept of penetrance captures the distinction between genetic variants contributing to Mendelian disorders and complex disease traits. Penetrance for a genetic mutation is defined as the proportion of individuals carrying a particular genetic mutation who also demonstrate the disease phenotype. The mutations that lead to Mendelian disorders have very high penetrances (approaching 100%) while for most variants contributing to complex disease, the penetrance is quite low. This concept will have significant relevance when we discuss utility of genetic screening.
The concept of genetic architecture describes the number of genes contributing to a disease trait, the number of variants per gene, and the magnitude of effect that each variant has on development of the trait. Although Mendelian disorders usually arise from inheritance of a single genetic mutation, many different individual genes may, when mutated, lead to a common disease phenotype (genetic heterogeneity). Furthermore, for any gene, many different mutations may also lead to the same disease phenotype (allelic heterogeneity). Both genetic and allelic heterogeneity introduce complexity when one goes about designing a genetic screening program for cardiomyopathies. Furthermore, although the penetrance of a disorder may be high, the exact manifestation of disease may vary from individual to individual, despite inheriting the same mutation (variable expressivity). A final level of complexity arises from the fact that multiple distinct diseases may share a common “low-resolution” phenotype, but in fact have a different pathologic basis (termed phenocopies), with potentially different disease course and treatment.
Genetic screening differs from clinical screening in several regards. Rather than serve as a way of diagnosing disease in asymptomatic individuals, the identification of a risk variant in an individual can give the probability of disease risk in individuals who may not yet have disease. Acting on this information may not only allow prevention of disease progression, but also the prevention of disease incidence, the “holy grail” of medicine. A second difference is that discovering that individuals with subclinical disease have a genetic risk variant may provide insight into the biological basis of disease for that individual. For clinically heterogeneous diseases, such as atherosclerosis or hypertension, understanding the driving pathophysiologic progress may allow targeted therapy that may surpass the efficacy of the “one treatment fits all” approach commonly used. Moreover, with some limitations, knowledge of the causal process may permit a more accurate prognosis of catastrophic outcomes such as sudden cardiac death or stroke and allow the focused implementation of screening or preventive therapeutic procedures that may be too costly or risky for the general population, but have high likelihood of benefit for a limited number of high risk individuals.
When should genetic screening used? An example may help illustrate the approach we use for potentially heritable disorders. Consider an individual with a disease that does not appear to be arising from any known environmental cause – in genetic studies, this individual is called the proband. An initial step should be to establish whether the disease is familial, as this has relevance to pursuing a genetic diagnosis for the individual, and on managing risk within family members. In addressing familiality, we must construct a careful family pedigree, asking about the health and manner of death of every relative. We need to be careful to distinguish two apparently similar situations, with considerably different ramifications: one where detailed pedigree information is available and no disease is apparent, versus another where there does not appear to be any other relative with the disorder but inadequate family history is obtained. Only in the former case could we conclude that the disease is not familial, and either sporadic or attributable to environmental factors. If the proband has multiple relatives with the disorder, we would consider it to be familial, and consider genetic screening.
The next considerations are related to our likelihood of identifying a causal variant in the proband. If the genetic architecture of the disease is such that there are a relatively small number of genes (low genetic heterogeneity) involved and there are causal genetic variants of moderate to high penetrance, genetic screening can be useful. Because many Mendelian disorders show significant allelic heterogeneity, screening for a single mutation tends to be unsuccessful, and sequencing of portions of the gene (exons, splice junctions) tend to be required to find likely causal variants. Several limitations exist with genetic testing of a single proband. Sequencing errors can occur, resulting in false positives and false negative results. Even with careful sequencing, a variant may be found in one of the candidate genes but not actually be causal for the disease. To establish a sequence variant as a potential mutation would require that it have the potential to have a deleterious effect (missense or nonsense) and lie within a protein domain previously attributed functional significance. A mutation that is falsely assigned causality and used for genetic screening in family members would lead to both false reassurance and false alarm, as the inheritance of the variant would have no bearing on the likelihood of developing the disease. This situation may be ameliorated if a large number of family members are available for genetic testing, as co-segregation of mutation with disease can be used to infer causality.
How useful would the identification of a genetic variant be? Because of the bewildering genetic and allelic heterogeneity of most Mendelian disorders, the individualized prognostication and treatment that was once hoped to follow genetic diagnoses has not materialized. We simply do not have enough prognostic information for individual mutations to provide mutation-specific predictions with any accuracy. As a result, the current utility of identifying a causal mutation in a proband is almost exclusively limited to facilitating screening of family members. In particular, with the help of genetic screening, we can help identifying affected individuals at a preclinical phase, or those with ambiguous clinical screening results.
A “cascade screening” approach allows an efficient method of evaluating which family members carry the causal allele. Once a genetic diagnosis of the proband is made, all of the first-degree relatives of the proband are screened. We can limit further genetic screening to first-degree relatives of the proband’s affect first-degree relatives. This process continues until no further affected individual is identified. Genetic diagnosis allows a considerable degree of reassurance to family members who are genotype-negative, as they no longer need clinical surveillance, and need not worry that disease will be passed on to their progeny. Conversely, a positive diagnosis in a clinically unaffected individual may lead to initiation of more frequent surveillance, avoidance of high risk behavior, implementation of preventive treatment, and potentially it may affect reproductive choices. Of course, as discussed above, the success of such an approach depends fully on confidence that the mutation used for screening is actually causal.
If a causal genetic variant cannot be definitively established for the proband, clinical screening should then be considered, as it can be useful in many of the same ways as genetic screening. Cascade screening, described above, cannot work for clinical screening because of incomplete age-dependent penetrance, which may lead to premature termination of screening if any individual failed to display features of the disease. Thus all relatives of the proband should be screened. The age of screening typically depends on the range of age of onset for the disease.
We can apply the above considerations to any disease with a heritable component. Below, we will address the screening approaches to dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular dysplasia (ARVD) and restrictive cardiomyopathy (RCM), highlighting how the known genetic architecture of the trait guides a genetic screening approach and how clinical characteristics of the disease influence a clinical screening approach.