For ‘Funsies’ or For Diagnoses? Recreational vs. Diagnostic Genetic Testing

1. For ‘Funsies’ or For Diagnoses? Recreational vs. Diagnostic Genetic Testing DNA Testing for General Curiosity We all know those people that pursue genetic testing "for fun." They want to learn about their ancestry or about unique traits, like whether they are more or less likely to have wet earwax. Genetic testing that is marketed and sold directly to the consumer, aka the public, is called "direct-to-consumer testing" or DTC testing. These types of tests are largely for non-medical, general wellness, or low risk medical purposes. Most DTC tests use a type of DNA technology called microarrays. Rather than reading through an individual’s DNA code letter by letter, microarrays often involve analyzing a multitude of single letters of DNA, also called single nucleotide polymorphisms, or SNPs (pronounced "snips"). SNPs occur normally throughout a person's DNA code. About 99.9% of the DNA is common for all humans, the remaining 0.1% are the SNPs that make humans unique, creating variation between the DNA code of one person from that of another. While most SNP's are linked to normal traits (hair color, eye color), some can be associated with diseases. For example, a single SNP in the F5 gene causes Factor V Leiden, a common genetic risk factor for blood clots. Whereas a combination of 88 SNPs working together can slightly increase or decrease a woman's risk for breast cancer1. A well-known example of a DTC test is 23andMe. The 23andMe test can be shipped directly to someone's home where they will spit in a tube and mail it back. It is with that small amount of saliva that the lab then extracts DNA for testing. Like with most DTCs, the testing done via 23andMe focuses on specific SNPs that are thought to be associated with certain traits, ancestry, and health conditions. Examples of health conditions include Alzheimer's, Parkinson's, and celiac disease. However, it's important to understand that while this type of test can be used for assessing genetic risk for developing these conditions it does not diagnose them. It's possible, for example, that someone has a risk variant associated with Alzheimer's but never ends up developing this disease. The reverse can be said as well- someone with Alzheimer's disease may not have an associated genetic variant. Testing for a Diagnosis In contrast, diagnostic genetic testing is done to actually diagnose someone with a medical condition- to be able to say, "Ms. Jane Doe has a diagnosis of hereditary breast and ovarian cancer syndrome."

2. Most often, diagnostic genetic testing is not just looking at SNPs throughout a gene or genes. Generally speaking, diagnostic genetic testing is using methods of reading through the genes in their entirety, letter by letter, looking for any misspellings (i.e. DNA mutations) or missing/extra parts (deletions/duplications). For example, a diagnosis of cystic fibrosis can be made by finding two mutations in the CFTR gene, one inherited from each parent. Similarly, a diagnosis of hereditary breast and ovarian cancer syndrome can be made by finding a single mutation in the BRCA1 gene. When testing for a diagnosis, typically the patient will be accompanied by a physician or a genetic counselor. Together they will evaluate the patient's medical and family history and will find the right genetic tests, or panels, for the patient. What to do with DTC results in a Genetics Clinic? In a genetics clinic, if a patient has a specific question or concern about a portion of their DTC results, a genetic counselor will often be able to address those. However, more often than not, patients are sent to a genetics clinic to discuss other diagnostic testing options. Further, most health-related findings on a DTC test should be confirmed in a clinical lab, especially those that will change decisions about medical treatment, such as results related to breast and ovarian cancer, for example. Case Example: A 25-year-old Northern European woman Lauren, a healthy 25-year-old female, was referred to a genetic counselor due to her family history of cancer. Lauren reports that her mother and maternal grandmother both died from breast cancer in their early 40s and that neither of them had genetic testing prior to their passing. She says to the genetic counselor, "My doctor told me to come here but I’m not really concerned. I had testing from 23andMe, so I know I’m BRCA1 and BRCA2 negative. There’s not much else we can do, right?" The genetic counselor pauses (and gasps internally!) and responds, "I’m glad you’ve come today to discuss your family history because there definitely is more testing that is indicated and that I would recommend for you." While 23andMe has started to analyze three SNPs within the BRCA1 and BRCA2 genes, these three SNPs correspond only to the three Ashkenazi Jewish founder mutations. Therefore, not only is this testing not relevant to an individual of non-Ashkenazi Jewish ancestry, but it does not even analyze the gene in its entirety. In addition, there are a handful of other genes, aside from BRCA1 and BRCA2, that could explain Lauren's family history of early onset breast cancer. The genetic counselor explains this to Lauren who agrees that more testing would be beneficial for her. She submits a sample to a lab that analyzes approximately 20 genes associated with hereditary breast cancer. Lo and behold, Lauren has a harmful (pathogenic) mutation in a gene

3. called PALB2 which significantly increases her risk for breast cancer, amongst others. This information allows the genetic counselor to discuss beneficial screening options with Lauren to help mitigate those risks. Take home message Not all genetic tests are created equal! Getting a DTC test might provide some information about ancestry or health conditions. However, that information can also be of limited clinical value, especially if the patient has not been assessed to understand what genes should be tested in the first place. Although DTC testing can include some diagnostic testing (ie. some mutations in BRCA1/2) it is not comprehensive, and it is not a substitute for taking a complete family history or undergoing clinical genetic testing under the supervision of a qualified specialist. A positive result from a DTC test can be life-saving since it can inform the patient of a possible condition and help the patient take action. However, like in our example of Lauren, a negative result from DTC genetic testing does not mean the patient is in the clear and shouldn’t be used to make decisions about medical treatment. The best advice for patients is to delve into their family medical history with a genetic risk assessment tool and ask a healthcare provider, such as a genetic counselor, for guidance in finding the right genetic test for them and their family.