Francis Collins, director of the U.S. National Human Genome Research Institute (NHGRI), stated that “…virtually every disease, with the possible exception of trauma, has a genetic basis.” However, genetic predisposition is not destiny.
In light of this statement, it is clear that genetic information plays a fundamental role in determining our health. In recent years, diagnostic systems based on DNA analysis have been developed that are capable of identifying the key factors in the development of a wide range of diseases.
Thanks to technological advances, these tools are now available to everyone; however, interpreting the results—and, consequently, understanding the information relevant to our health—is not always easy for laypeople. In particular, the concepts of heredity, family history, and predisposition are fundamental to understanding the purpose and results of a DNA test.
The term “heredity” refers to one or more identifiable genetic mutations that can be passed on to one’s offspring and that lead to the development of a specific disease. When we speak of hereditary diseases, we are referring specifically to monogenic diseases in the strict sense, such as cystic fibrosis or sickle cell anemia, which are inherited in a Mendelian manner. In this case, there is a cause-and-effect relationship between the presence of a specific genetic mutation and the disease. This is the typical focus of diagnostic and screening tests.
Diagnostic tests are designed to identify genetic mutations responsible for a confirmed or suspected disease and have a well-defined molecular target. Screening tests are similar to diagnostic tests in that they also have well-defined molecular targets, but they are designed to identify carriers of recessive genetic mutations—mutations that can cause the disease to manifest in the offspring of the individuals being tested. These tests allow for a clear and understandable interpretation, since once the genetic factor under investigation is identified, the link to the disease is direct.
“Familial” refers to a situation in which there have been multiple cases of a specific disease in a family’s history without a recognized genetic cause. Family history and heredity are therefore not synonymous, since the modes of hereditary transmission can be assessed within known genetic mechanisms, whereas this is not the case with family history.
When we talk about predisposition (or susceptibility), we mean the risk of developing a specific disease. In this case, the presence of known mutations (which in this context would more accurately be called genetic variants or genetic polymorphisms) is not in itself sufficient to cause the development of the condition; rather, it is triggered by the presence of concomitant environmental factors (poor diet and lifestyle, etc.). This is typically the case with chronic degenerative diseases (type 2 diabetes, celiac disease, cardiovascular diseases, most forms of cancer, and Alzheimer’s disease, etc.). In this case, the risk is determined by the simultaneous presence of numerous genetic variants, which—depending on the disease—are only partially understood.
Similarly, the role of environmental triggers and how they interact with genetic factors in the development of the disease is not always known. Certain types of cancer lie at the intersection of heredity and predisposition (a typical example is the role of the BRCA1 and BRCA2 genes in breast cancer, a case made famous by actress Angelina Jolie), in which the presence of a specific mutation greatly increases the risk of developing the disease (up to an 87% probability in the case of mutations in both genes, Judkins T et al. Cancer 2012;118(21):5210-6), though it is not the sole cause.
Genetic predisposition is the focus of predictive or genetic susceptibility testing. In this case, the tests are aimed at the molecular identification of genetic variants (typically numerous) linked to the development of a specific disease and indicate an increased (or decreased) risk compared to the general population. This risk should not be understood in absolute terms, as the tests do not identify the environmental factors that contribute to the development of the disease. In light of this, it is clear that one can have a high predisposition or susceptibility but never actually develop the disease. Predictive tests are therefore designed to identify the “weak points” in our bodies with the aim of implementing preventive measures to minimize environmental risk, which is an essential cofactor in the onset of the disease.
