Knowledge is power. Sometimes, it’s the power to save lives. In 2013, a group of specialists in medicine and genetics published a list of genetic conditions that, if identified early, can be largely mitigated (or, in some cases, avoided entirely). It’s currently estimated that approximately 3% of the US population—nearly 10 million people—has a variant in one of these genes.
This list of genes is currently called the ACMG 59, and Helix will soon offer a product that tests for it in collaboration with our partner PerkinElmer Genomics.
What types of conditions are on the ACMG 59 list? At a high level, it contains three types of conditions: cancer predispositions, cardiovascular predispositions, and metabolic conditions. While most of these conditions are inherited in an autosomal dominant fashion, some are inherited in an autosomal recessive or X-linked recessive pattern. In all three cases, knowing about these conditions ahead of time can give you the power to make informed decisions and potentially avoid health complications.
Variants in more than 20 of the genes on the ACMG 59 list cause a cancer “predisposition,” meaning people who inherit any one of these variants have an increased risk or likelihood of developing cancer when compared to the general population. Most of these variants make someone more likely to develop cancer, but they don’t guarantee cancer development.
Most of these genes are involved in a process known as DNA damage repair. Cancer develops when somatic mutations—changes in the DNA that aren’t heritable—accumulate in a cell that force it to behave abnormally. Genes regulating DNA damage repair play an important role in preventing mutations. Because of this, variants in the DNA that prevent or hinder their ability to repair the DNA can lead to an increased chance of mutation and thus cancer development. The most well-known DNA damage repair genes on this list are the BRCA genes; when a person has a variant in BRCA1 or BRCA2, the odds of developing breast, ovarian, or prostate cancer (among other forms) are increased. For these genes, the odds of cancer increase over the odds in the general population. Some reports show 5 or 6 times as much risk for breast cancer, but the odds are different for each organ.
So how would knowing if you had a variant in one of these genes help you and your family? Through screening and prevention. Screening, in this context, basically means “catch the cancer as early as possible so it’s more likely to be treatable.” Prevention, much like it sounds, is about preventing the cancer from happening at all. Techniques for screening and prevention can involve things like imaging technology, such as MRIs or mammograms, blood tests, or preventative surgery. Ultimately, the goal here is to identify people who can benefit from techniques like these and prevent cancer development or progression.
Over 30 of the genes on the ACMG 59 list are associated with cardiovascular conditions. Much like the cancer conditions on the list, they also cause a “predisposition,” meaning increased odds of having a cardiovascular complication when a person inherits a variant in one of these genes. In this case, most of these genes have some role to play in regulating one of the following: cholesterol levels, electrical properties of the heart, aorta function and integrity, or the size of muscles in the heart. A variant in one of these genes could have a number of different effects including elevation of cholesterol, an abnormal rhythm of the heart, or even failure of the heart to pump blood. If not identified early, individuals with one of these conditions could experience a sudden cardiac arrest that in many cases is lethal.
An EKG, or ECG, is a type of test routinely used to monitor a person’s heart health. EKG stands for electrocardiogram—the “k” relates to the Greek root word for heart, which is kardio. This test measures the electrical activity of the heart and can be used to identify atypical heart rhythms and other potential problems.
Identifying variants in these genes early allows you to consider screening and preventive steps for these types of conditions. The goal of prevention in this case is to lower the odds of the sudden cardiac arrest or decrease the life threatening effects of it. In either case, the method of prevention depends on the gene involved. Medications, surgery, or an implantable cardiac defibrillator all may be options. Screening usually involves some form of imaging, like an EKG, an echocardiogram, or an MRI of the heart. Once you know the gene and variant, you can know which type of cardiovascular condition to watch out for, and tailor the screening and prevention accordingly.
A metabolic condition can be any of a group of conditions caused by the malfunction of an enzyme—a class of proteins that actively participate in cellular activities, particularly chemical reactions. Consider the conversion of a hypothetical molecule A into molecule B. Enzymes make it easier for a cell to turn molecule A into molecule B. When a person inherits a variant in their DNA that diminishes or alters an enzyme’s activity, it can then alter the levels of these molecules. In our hypothetical example above, a variant that diminishes the enzyme’s ability to convert A into B would result in an accumulation of A and a lack of B. Depending on what those molecules are, the buildup of A or the lack of B can have a negative impact on the cell and result in medical conditions.
One example is Fabry disease, which is caused by a build-up of the input molecule (in this case, globotriaosylceramide). As this molecule builds up throughout the body, it can cause medical issues in multiple organs, including the heart and kidney. A person can develop medical problems for years before they become diagnosed with Fabry, which is treatable by Enzyme Replacement Therapy (ERT). In ERT, the needed enzyme is created in a lab and given to people in regular injections. It cannot reverse the damage caused by Fabry disease that already happened, but can keep the condition from progressing—thus, early detection is critical.
This is by no means an exhaustive review of the ACMG 59. But we did want to make sure that it’s clear how much progress has been made in piecing together genetics—along with modern medical imaging, advanced medical devices, FDA approved biologics, and surgical techniques—to help people lead fuller, longer lives. In addition to the information offered by an ACMG 59 test, genetic counselors are available to help people understand how it pertains to them and make informed choices.