What is the difference between the genetic testing done at a hospital clinic and personal genetic testing services like 23andme?

Late in 2013, the American Food and Drug Administration barred the personal genetics firm 23andme from offering health reports to its clients. Does this mean that genetic testing is unreliable? The answer is a clear no, but the case is an opportunity to talk about the different ways that genetic information is now being used and the methods used to do that testing.

The company 23andme has been known primarily as a supplier of ancestry information. For people tracking their family tree, the company does an analysis of the person’s DNA on a submitted sample of salvia and offers estimates about how much of a person’s ancestry is Native American or African, or European. However in recent years, the company has begun offering additional components to its reports – including more and more extensive health reports.

Before the company was forced to discontinue its genetic health reports, users who purchased the analysis were also offered estimates about their risk of developing common diseases such as diabetes, high cholesterol, Alzheimer disease and age-related macular degeneration (AMD).   The reports did not address rare inherited conditions such as retinitis pigmentosa or inherited macular dystrophies such as Stargardt disease. The reports also suggested a person’s sensitivity (or lack thereof) to certain medications such as anti-clotting drugs. The Food and Drug Administration forced the company to discontinue these reports, because 23andme had not submitted their tests for approval as a medical device, a process necessary for all tests used to make a medical diagnosis. Without such an application, the FDA did not have sufficient information to determine that the information being provided to people was accurate. The FDA was concerned that the reports might lead people to make dangerous health choices – such as changing their dosage of one of the medications profiled.

There are key differences between the tests done by 23andme and the tests you could receive through a hospital-based genetics clinic. First of all, the tests used by these clinics have been approved as medical diagnostic tools in Canada, or if the test is sent to the USA or other countries, by the appropriate authorities. The technology is also very different.

What does 23andme test?

Your DNA is made up of over 3 billion nucleotides, the basic building blocks of our genes. 23andme screens for about 1 million specific changes in these nucleotides.  Sometimes a change occurs in the DNA as it is copied when cells reproduce. Such DNA changes can be passed on from parent to child. Most DNA changes, which geneticists call SNPs (pronounced snips) are normal variations and do not cause medical health issues. If a change does cause a health problem, it is usually referred to as a mutation. If two people have a similar pattern of changes in the SNPs selected by 23andme they are probably closely related. This is how 23andme determines ancestry.

Some of the SNP changes selected by 23andme are associated with particular illnesses, although for complex diseases like heart disease or Alzheimer disease, many different genetic changes can influence the course of the disease. People’s lifestyle – diet, exercise, exposure to toxins, all also influence these conditions.  This is still a relatively new science and there is lots of debate about which genetic changes matter most and how much they matter. 23andme’s results are based on their interpretation of a few particular SNPs they have selected to analyze for each condition.

What happens when you visit a clinic for genetic testing for a genetic disease?

The 23andme process is very different from what happens if you are referred by your eye doctor for genetic counselling and genetic testing. The 23andme testing is predictive. It is looking at complicated conditions that are influenced by the presence of many different genes, as well as environmental factors, and trying to determine how these genes will interact to shap a person's risk. In the circumstance of genetic testing for inherited retinal disease, the testing is trying to find a specific mutation that is causing the symptoms you already have. Although there are many different genes that can cause inherited diseases like retinitis pigmentosa or Usher syndrome, each person affected by these conditions only carries a single mutation.There are two ways that genetic testing for inherited retinal conditions can be done.

In the past, gene testing looked for specific known mutations in specific genes, mutations that had been found in other people with your condition. So if you have the symptoms of a condition like Usher syndrome and the test finds one of the known mutations, your diagnosis is confirmed. Tests would always be run with control samples from people who did not have Usher syndrome (and therefore don’t have the mutation) to be sure the test is working correctly. This kind of testing is still used to test family members of a person who has an eye disease. In this case, the test simply looks to see if you have the same mutation(s) that is causing the condition in your family member. If it is not there, you are not at risk.

However, in many cases, people with retinal disease did not receive results from this initial form of testing because their condition was due to a mutation that was not yet known. In the past few years, most genetic services have come to use sequencing to look for mutations. Sequencing is a much more detailed process that looks for changes in every single nucleotide in the portion of your DNA where your symptoms suggest that a mutation is most likely. The changes found by sequencing can be known mutations or normal variations (SNPs), but often they are labeled on the laboratory report as “variations of unknown significance” or VUS for short.

Health care professionals who specialize in genetics then begin investigations to determine whether or not these changes should be consider SNPs or causative mutations. They may start by doing research on professional websites that document mutations and SNPs. They may ask other affected and unaffected members of your family to be tested in order to help sort out normal variations. With their help and expertise many more people are now successfully receiving a genetic diagnosis for inherited retinal conditions and more mutations are being discovered

In the very near future, the genetic testing process may change again and begin to rely on sequencing the affected person’s entire DNA, a process known as whole genome sequencing (WGS). This approach is becoming more cost effective, but access is still limited due to the ethical issues involved and difficulties with interpretation of data. If whole genome sequencing is used to evaluate your DNA, there is the potential to find out about any genetic disease not just the eye disease you are testing for. This may be information you don’t wish to know. For example, you may want to choose just to have just retinal genes analyzed or you may request your risk for other specific diseases like breast cancer be determined. To facility such choices, all genes might be sequenced but only a particular portion might be analyzed.   At present, health care providers prefer to analyze only specific genes related to symptoms and specific genes that are “medically actionable” with some sort of screening or treatment plan. 

Whole genome sequencing is a strategy that usually requires DNA from your parents as well as samples of the affected person’s DNA. Use of whole genome sequencing will likely accelerate the discovery of new gene mutations that cause retinal disease.

What about genetic testing for age-related macular degeneration?

Unlike testing for inherited retinal diseases, genetic testing for AMD is about trying to predict the risk of developing a complex disease from specific genetic test results. This is difficult, because while we know that AMD is influenced by genetics, we also know that lifestyle factors, including smoking and sun exposure, can influence a person’s risk. Some DNA changes have been identified that increase a person’s risk of developing AMD, and comprehensive testing is available to look at many of these genes, but there is a lot of knowledge still required for clear cut answers for AMD. We know that when these changes are inherited in families that multiple family members often develop AMD. However we also know that changes in diet and lifestyle can help reduce these risks and may have a bigger impact than genetics. Most health care providers with a genetics specialty feel that people, whether they have a family history of AMD or not, should simply be advised to protect themselves through diet and lifestyle changes, especially smoking reduction.

In November 2012, the American Academy of Ophthalmology recommended against using genetic tests to try and predict AMD risk. However they did encourage further research and note that genetic testing might be useful in the future. For example, there is some evidence that people with certain genetic mutations may be more readily treated with particular types of therapies. In the future, genetic tests may be used to help determine the best treatments for a patient. There may also be situations, where there is a strong family history of AMD, when it may be helpful to have a genetic measure of risk for younger family members as added incentive to make the suggested life style choices.

Whether you should consider genetic testing for AMD based on your family history is something that you can discuss with your doctor, so that the advice you get is tailored to your situation. You can be confident that when your family doctor or ophthalmologist refers you to one of Canada’s Medical Genetics Clinics for genetic counseling and genetic testing, you will be able to access the help and support of a trained counsellor who can help select the testing that will give you the most possible information and will help you interpret the results you receive.

For more about genetic testing, you can see our factsheet on genetic testing for inherited retinal conditions, or see responses to other common questions about genetic testing.

Written January 13, 2014. Reviewed by Joanne Sutherland, genetic counsellor, Department of Ophthalmology at the Hospital for Sick Children in Toronto.

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