Consumer genetic testing for health conditions has always been viewed with some skepticism by healthcare professionals. For many, direct-to-consumer (DTC) genetic testing was synonymous with 23andMe, whose health-related products are perceived as having little to no value for health care. But the landscape for consumer-initiated genetic health testing has changed dramatically in just the last year.
The number of companies in this space has mushroomed to at least nine (depending on who you count). Moreover, the tests offered by many of these companies are the same clinical-grade tests you can get through your physician. For consumers, this means more choices and better products. For healthcare providers, it means it’s time to brush up on your genetics.
I use the term consumer-initiated (others may use ‘patient-initiated’ or ‘direct-to-consumer’) to distinguish it from a genetic test that is initiated in the course of medical care by the patient’s own healthcare provider (sometimes called physician-initiated).
By a genetic health test, I mean a genetic test that is used to identify individuals with or at risk of a medical condition. This is to distinguish it from a genetic test that, for example, tells patients what diet will purportedly work for them, what vitamins they should be taking or what fitness program suits them best.
With the growing number of options for patients to receive genetic health information outside of their medical home, and with the holidays approaching, it seems like a good time to review the players in this space, the types of tests they offer and their quality.
Characteristics of consumer-initiated tests
Healthcare provider involvement
The traditional genetic testing model is one where the patient’s physician orders a genetic test, receives the results and shares them with the patient in the course of their medical care. Consumer-initiated testing models turn the physician-patient relationship on its head, putting the patient in charge of ordering and receiving results, which they may or may not share with their physician.
Consumer-initiated testing is offered via one of two models: 1. where there is no healthcare provider involvement whatsoever; or 2. where there is involvement of a third-party healthcare intermediary.
In 2013, the FDA cracked down on all companies who were offering health-related tests directly to consumers without any healthcare provider oversight. Only one of these companies, 23andMe, went on to comply with FDA requirements in order to obtain clearance of their health-related tests. As such, they remain the only consumer-initiated genetic testing company whose health-related tests are allowed to be offered to consumers with no healthcare provider involvement.
The majority of players in this space involve third party healthcare providers in the process. This usually includes a physician who reviews the order and test results, as well as access to a genetic counselor. Those healthcare providers might be employees of the genetic testing lab, but more often than not, the testing labs are outsourcing this work to provider networks like PWNHealth, Genome Medical and others who utilize tele-health models to reach customers remotely.
Quality and completeness
The quality of a genetic test is determined in large part by how well it can identify any of the generally large number of clinically relevant pathogenic variants in a gene (i.e. its clinical sensitivity). This is sometimes described as the completeness of the test (explored in more detail in a separate paper).
A test that detects or reports on only a subset of clinically relevant variants is incomplete and can result in false negative results. In other words, the person is told they don’t have a genetic variant, when in fact they do. Not only is this a missed opportunity to manage and potentially prevent a genetic disease but may cause a false sense of invulnerability and negatively impact health behaviors.
There are varying degrees of completeness of genetic tests. Genotyping arrays, used by most of the ancestry testing companies, are an inexpensive method to query large numbers of pre-specified gene variants in a single test. However, these arrays contain few of the important pathogenic variants for hereditary conditions.
The most complete tests generally utilize multiple variant detection methods including high-throughput next-generation sequencing. Sequencing is generally performed on a panel of genes (e.g. all hereditary cancer genes), or the entire exome (all genes) or entire genome (all gene and non-genic regions) of an individual.
Novel variants found in disease genes require interpretation to determine if they are disease-causing, or pathogenic. As this can be labor intensive and expensive, some labs might forego this step and sequence an entire gene but only report out on a subset of known, well-established pathogenic variants. For the purpose of genetic testing in a healthy population setting, this may be good enough.
However, some tests are so incomplete that their clinical usefulness is compromised considerably. For example, a study from Invitae found that 23andMe’s hereditary breast cancer three-variant test misses nearly 90 percent of BRCA gene mutation carriers. These tests result in a high false negative rate and pose a substantial risk to patients and providers who may not understand their very limited performance.
Most commonly offered health tests
Companies that provide consumer-initiated genetic health testing are more or less consistent in what tests they offer. The most common tests include those for hereditary cancers, hereditary cardiovascular diseases and carrier testing. Other tests include those for medication response (pharmacogenomics), rare diseases in newborns, and for common diseases (including polygenic risk scores).
Hereditary Cancers
Approximately 5-10% of cancers are thought to be hereditary, where an inherited mutation in a cancer-causing gene greatly increases a person’s risk of developing cancer in their lifetime. Most hereditary cancers are part of syndromes that can manifest in different ways in different patients. For example, Hereditary Breast and Ovarian Cancer (HBOC) Syndrome is usually diagnosed in women with breast or ovarian cancer, but mutations in the underlying genes can also increase risk of prostate and pancreatic cancers.
Similarly, Lynch Syndrome is a hereditary form of colorectal cancer but also increases risk of endometrial, gastric, ovarian and other cancers. There are a couple of dozen well-established hereditary cancer syndromes, some of which can be caused by more than one gene.
Hereditary Cardiovascular (Heart) Diseases
About 5-10% of cardiovascular diseases (CVD) are thought to be hereditary, including inherited forms of hypercholesterolemia (Familial Hypercholesterolemia), cardiomyopathies (e.g. Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy) and arrhythmias (e.g. LongQT Syndrome).
Mutations in genes underlying these conditions usually increase a person’s lifetime risk of these disorders greatly. There are also some hereditary disorders, like hereditary hemochromatosis, and venous thromboembolism, that can also increase a person’s risk of CVD, although by not as much.
Carrier Testing
Carrier testing generally refers to testing for rare recessive disorders, in which a patient needs to inherit a mutated gene from both parents in order to develop the disease. Most people who undergo testing are healthy couples and wish to know if either or both of them carry a single mutated gene that they might pass on to their offspring. When both partners carry a mutation, their risk of having an affected child is 25%.
Testing is often done in the context of family planning. Occasionally carriers of one mutated gene exhibit mild symptoms of the disease or perhaps an unrelated condition, but generally speaking, carriers are considered unaffected.
The three disorders that are most commonly tested for in medical practice are cystic fibrosis, sickle cell anemia and Tay-Sachs. However, in recent years as knowledge of the genetic basis of many rare recessive disorders has grown, carrier testing panels have expanded, sometimes testing up to hundreds of conditions.
Newborn screening/rare disease
State-run newborn screening programs in the US involve compulsory testing of all newborns for a minimum of 34 genetic conditions where early treatment has been shown to minimize morbidity and mortality. Many of these are metabolic disorders and are detected using mass spectrometry and not genetic analysis.
As the rate of discovery of genes underlying rare diseases of childhood has grown to about 200/year, some commercial labs have begun offering expanded newborn screening genetic tests as an adjunct. The consumer-initiated versions of these tests have only come to market recently.
Medication Response (Pharmacogenomics)
Pharmacogenomic tests are available for some drugs to determine, based on the patient’s genetic makeup, whether the drug is appropriate, the best dose or the likelihood that the patient will develop an adverse drug reaction. The most commonly tested genes are the cytochrome P450 genes (CYP2D6, CYP2C9, CYP2C19) and some of the HLA genes. The number of companies offering these tests directly to consumers has dwindled as the FDA has stepped into to regulate them.
Polygenic Risk Scores
A polygenic risk score (PRS) is a type of test that examines many genetic variants simultaneously and combines the results into a single risk predictor. A very small percent of people obtain results that indicate they are at greatly increased risk of a disease. Most people obtain results that indicate only a modest increased or decreased risk of disease. These tests are slowly making their way into clinical use but are not yet widely available.
ACMG59 genes
The American College of Medical Genetics (ACMG) published a list of 59 genes underlying inherited conditions that they recommend reporting to patients if they are found incidentally in the course of whole genome or exome sequencing undertaken for a different purpose. The ACMG59 list is considered by many to be the best compilation of genes underlying serious conditions where the genetic test results are actionable. The 59 genes include 25 genes for hereditary cancers, 30 genes for hereditary CVDs and 4 genes for other conditions.
Other random tests
Besides the broad test categories listed above, some labs offer tests that can show an increased risk for a variety of other disorders like Alzheimer disease, Parkinson disease, macular degeneration, celiac disease and more.
The Players
The consumer-initiated genetic health testing market used to be dominated by a couple of players, but in 2019 the field expanded dramatically. Companies already in the business of offering clinical-grade genetic tests joined the field to give consumers more options for high quality testing. Others are likely to follow suit. The table below includes the companies and tests that they offer directly to consumers.
Next-generation sequencing (NGS); NGS with additional methods (NGS+); known pathogenics (KPs); cardiovascular disease (CVD); newborn screening (NBS); pharmacogenomics (PGx); polygenic risk score (PRS)
Color Genomics
Color Genomics really pioneered the model of consumer-initiated testing with a third-party physician intermediary. They offer complete, high sensitivity diagnostic grade tests for cancers, CVDs and pharmacogenomics called Color Extended. Their primary business is consumer-initiated testing (directly or through employee health benefit programs) and population health genetic testing.
Invitae
Their primary business is physician-initiated where they offer a wide range of diagnostic-grade genetic tests. They recently entered the consumer-initiated space with Genetic Health Screen, a product that bundles tests for cancers, CVDs and carrier testing (they can also be ordered separately). Their screening test is the same complete, high sensitivity test that a physician would order, although variants of uncertain significance (VUS) are not reported.
Picture Genetics (Fulgent Genetics)
A new consumer-facing offshoot of the company Fulgent Genetics, whose primary business is in physician-initiated testing for a wide range of genetic conditions. Picture has three products, a carrier screening test, Picture Parenting, a rare disease/newborn screening test, Picture Newborn, and Picture Wellness, which covers the ACMG59 panel. The tests are the same complete, high sensitivity diagnostic-grade tests that a physician would order.
Sema4
Their primary business includes clinical grade genetic testing for a moderate range of conditions. Their consumer-initiated offering consists of one test, Natalis, which includes both a rare disease newborn/childhood testing panel and pharmacogenomic testing for children. The rare disease panel reports only known pathogenic variants.
Veritas Genetics
The only consumer-initiated testing company based on whole genome sequencing (as opposed to whole exome, panels or genotyping array). Their MyGenome product reports on hereditary cancers, CVDs, carrier testing and other diseases. Their standard test only reports known pathogenic variants, but with their premium service, they offer more complete, high sensitivity diagnostic grade testing.
Helix
The Helix business model is unique from other consumer-initiated testing companies in that they offer a marketplace of apps developed by other companies to analyze segments of the genome. Genetic analysis is based on whole exome plus a genotyping array. Currently the two most useful health product apps include CarrierCheck, a carrier screening test from Sema4 that reports only known pathogenic variants and Perkin Elmer’s GenePrism: Actionable Insights a complete, high sensitivity panel including the ACMG59 genes.
23andMe
One of the pioneers of consumer genetic testing, 23andMe, is the only company to have received FDA approval for their genetic health tests. They use a genotyping array and offer a mix of tests which include variants that increase risk of disease modestly as well as high risk pathogenic variants for rare genetic diseases. They also offer a polygenic risk score test for diabetes. Their pharmacogenomic test has been FDA approved, but as of writing it is not available to customers. Their Carrier Status and Genetic Health Risk tests are mostly incomplete, detecting only a very small fraction of known pathogenic variants in some cases. As such, a warning states that their tests should not be used for making medical decisions.
Ancestry
The most recent entrant into this space, Ancestry.com currently uses a genotyping array and offer a mix of tests in their AncestryHealth Core product which include variants that increase risk of disease modestly as well as high risk pathogenic variants for rare genetic diseases. Their gene list is focused on some of the most actionable genes and diseases. The Core test covers only a small number of known pathogenic variants in a minimal set of genes, making it of limited clinical value. They are planning to offer an exome sequencing-based test in the coming months, AncestryHealth Plus, which will cover the same genes but detect more variants and thus improving the medical utility.
MyHeritage
This Israeli company’s DNA Health test closely resembles 23andMe’s with respect to both the diseases it tests for as well as the limited number of variants in each gene. They offer three different polygenic risk score tests for different conditions as well. The biggest difference between these tests and 23andMe’s health tests is that there is a third-party healthcare intermediary involved. This does not alter the very limited clinical value that their test provides.
Third party analysis companies
Besides the tests mentioned so far, many of which represent clinical grade testing options, there are several that we haven’t mentioned, including those offered by Nutrahacker, Livewello, Sequencing.com, DNA Doctor, Dnomium, Genetic Genie and many others. These companies offer health-related tests through third party analysis of raw data from 23andMe, Ancestry and others. The dangers of third party analysis were captured in a recent research paper that found very high rates of analytical false positives (40%) and variant misclassification (25%). These products have very limited analytical validity, clinical validity and utility and pose a high risk to consumers.
Impact of consumer genetic testing on healthcare providers
Companies offering genetic health tests to consumers are betting that including a physician intermediary in the ordering and reporting process will mitigate the risks associated with these tests. While some healthcare provider involvement is better than none, going outside of the medical home for genetic health information leaves a gap in the continuity of care that a patient receives.
Healthcare providers should be prepared to manage their patients who come to them with genetic test results. A recent study by Kaiser Permanente found 35% of physicians had at least one patient bring DTC genetic test results to them in the past year. This is only going to grow with increased access to consumer-initiated testing.
This same article describes how among physicians receiving DTC genetic test results from their patients, 40% made one or more referrals, the most frequent being to clinical genetics. With the increased access to genetic counselors through the companies offering genetic tests, a referral to clinical genetics at the patient’s medical home would now seem redundant.
Ultimately, it’s the physician who will need ‘counseling’ about the value and legitimacy of different consumer-initiated tests, the significance of the test results and how to manage their patients based on this information.
Learn More
To learn more about genetic testing and improve your genomic literacy, check out our online courses at precisionmedicineacademy.org.
Precision Medicine Advisors specializes in communicating precision medicine to lay professional audiences, providing scientifically sound, unbiased information to promote the responsible use of genomics in medicine.
Contact info: jeanette@pmedadvisors.com