The pitfalls of DTC testing

Let’s dive straight in.

Disease inheritance is occasionally a simple matter of carrying the variant that causes the disease. But, contrary to popular belief, in many other cases, it is not a simple linear process.

Many gene variants instead are risk factors that predispose a person carrying them to a certain condition, but there may be interactions both with other genes and with the environment and time which determines the biological outcome.

GWAS techniques

These variants are identified by genome-wide association studies (GWAS) and are commonly checked for in DTC panel tests. The predictive power of such associations is low if there is no family history of the condition.

The figure in this article on Multifactorial inheritance and genetic disease shows what can and can’t be detected using GWAS techniques.

Variable penetrance

GWA studies result in a polygenic risk score combining many different common variants to put the patient in a risk category eg for developing diabetes. The validity and utility of this risk score for predicting clinical outcomes are unclear.

In any case, ideally, the risk score should be evaluated against average population risk and take into account other factors such as family history so that guidance can be provided individually to assess the risk and make a health promotion plan to avoid the unwanted outcome.

Even for Mendelian disease, a DTC test result can be misleading as the SNP-chip genotyping which is typically used checks for the presence of a specific limited number of variants in the test DNA.

False negatives

In a disease such as breast cancer, the main BRCA variants will be tested for and may not be found, but rarer variants (and currently undiscovered ones) will not be part of the test panel so the patient may be falsely reassured that they are not carrying this risk, i.e. receive a false negative result.

False positives

In addition, very rare variants that are detected are often false positives (due to errors in sequencing) and are not really present in the person’s DNA.