Direct-to-consumer constitutional (germline) genomic testing

Traditionally, constitutional (germline) genomic testing is facilitated by a trained clinician or genetic counsellor, whose role is to make sure that the test is clinically appropriate, that the patient understands the implications and results of the test, and that patient consent is well-informed and provided voluntarily by an individual with appropriate capacity.

Direct-to-consumer (DTC) testing companies bypass these processes by dealing directly with the patient. The patient supplies a sample, usually saliva, from which their DNA is extracted. The company will then test the DNA and send back a written report of the results. Additionally, the patient may request their raw sequencing data from the company, which can then be sent to a third party company for additional analysis.

Most companies offer tests for a combination of the following:

• ancestry testing, giving information about a person’s heritage and ethnicity;
• genetic predisposition to certain disease (most DTC tests look at common variations that may have a slight influence on the risk of common complex conditions);
• carrier testing for inherited conditions such as cystic fibrosis and sickle cell disease;
• certain variants within known disease-causing genes, such as the familial breast and ovarian cancer susceptibility genes BRCA1 and BRCA2;
• certain traits such as taste preferences, hair loss and lactose digestion; and
• variants that might influence drug metabolism (pharmacogenomics).

• Some DTC tests use arrays (or ‘chips’) to detect single nucleotide polymorphisms (SNPs). SNPs of interest have largely been identified through genome-wide association studies, many of which have been undertaken in white European populations.
  • The majority of these SNPs are individually associated with tiny disease risks, and are best interpreted in the wider context of other genomic, environmental and lifestyle risk factors.
  • Disease associations may not necessarily be the same across different ethnicities.
  • The reliability of these SNP chips is very limited for rare variants with a frequency of less than 1 in 50,000 (sensitivity of about 16%).
• DTC carrier testing for high-risk variants associated with inherited conditions is often incomplete, usually only testing for a few common variants, and can be falsely reassuring. For example, some companies offer BRCA gene testing that only tests for the three variants most common within the Ashkenazi Jewish population, out of thousands of possible variants.
• High false positive rates have been reported for variants detected following analysis of raw DTC sequencing data by a third party company. Variants identified in this manner should be validated in a clinical laboratory before any change in management is recommended. Complications arise if the patient does not qualify for NHS-funded genomic testing.
• The positive identification of a genomic biomarker does not automatically mean that a patient will be eligible for a targeted treatment; access to treatments will depend on the drug licensing approvals and NHS funding agreements.
• There is a lack of formal genomic counselling around the testing process. This is particularly important for the risk profile reports for conditions such as Alzheimer’s disease. If an individual is embarking on DTC for a ‘bit of fun’ and, through the process, is informed of a significantly increased risk of cancer or Alzheimer’s disease, they are likely to be unprepared for this information.
• Incidental or unexpected findings can emerge, such as non-paternity, unexpected half-siblings and carrier status.
• There are concerns around genomic data privacy.

• If a particular result is bothering your patient, have a look at the small print. It may be that the ‘increased risk’ is actually very small in terms of individual relative risk and they can be reassured.
• Encourage your patient to remember that lifestyle factors, such as smoking and diet, outweigh small genomic variants in terms of risk of developing common complex diseases, and that these factors should be their focus.
• If your patient underwent DTC testing as a route to carrier testing (for example, if they have a family history of breast and ovarian cancer and want to know their BRCA status), do not assume that the testing that has been done is complete or that the results are accurate. No clinical action should be taken based on results from DTC testing. Only results that have been obtained from a formal diagnostic laboratory should be used to determine management or plan preventative strategies. If the patient is eligible for formal NHS testing, they should be referred according to usual guidelines and eligibility, regardless of DTC results. The patient may be ineligible for NHS-funded genomic testing, however, and you may wish to speak to your local clinical genetics service to determine whether a referral is warranted.

• Direct-to-consumer (DTC) genomic testing is genomic testing of any type that can be arranged directly by the individual, without being ordered by a clinician or genetic counsellor.
• In dealing directly with the consumer, DTC testing companies bypass procedures practiced by the NHS to ensure, for example, clinical appropriateness of the test and that patient consent is well informed.
• Pitfalls of DTC testing include a lack of formal genomic counselling, a high rate of false positive results for some tests, and the fact that carrier testing for high-risk variants is often incomplete, thereby providing false reassurance.
• No clinical action should be taken based on results from DTC testing. Only results that have been obtained from a formal diagnostic laboratory should be used to determine management or plan preventative strategies.

For clinicians

• The Guardian Science Weekly podcast, 11 October 2019: The dangers of DIY genetic testing (audio, 28 minutes, 26 seconds)
• The Royal College of General Practitioners and the British Society for Genetic Medicine: Genomic position statement

References:

• Burton A. ‘Are we ready for direct-to-consumer genetic testing?‘ The Lancet Neurology 2015: volume 14, issue 2, pages 138–139. DOI: 10.1016/S1474-4422(15)70003-7
• Horton R, Crawford G, Freeman L and others. ‘Direct-to-consumer genetic testing‘. British Medical Journal 2019: volume 367, article l5,688. DOI: 10.1136/bmj.l5688
• Mahase E. ‘GPs are advised to ignore genetic test results that have no clinical basis‘. British Medical Journal 2019; volume 5, issue 367, article l16,374. DOI: 10.1136/bmj.l6374
• Tandy-Connor S, Guiltinan J, Krempely K and others. ‘False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care‘. Genetics in Medicine 2018: volume 20, issue 12, pages 1,515–1,521. DOI: 10.1038/gim.2018.38
• Weedon MN, Jackson L, Harrison JW and others. ‘Use of SNP chips to detect rare pathogenic variants: Retrospective, population based diagnostic evaluation‘. British Medical Journal 2021: volume 15, issue 372, article n214. DOI: 10.1136/bmj.n214

For patients

• The Guardian Science Weekly podcast, 11 October 2019: The dangers of DIY genetic testing (audio, 28 minutes, 26 seconds)