Misinterpretation of direct-to-consumer (DTC) genetic testing results could pose a clinical risk to individuals, according to a case study published in Clinical Pharmacology & Therapeutics. In the reported case, rare genotypes for the gene encoding thiopurine methyltransferase (TPMT) were misinterpreted by a DTC company and could have affected dosing treatment decisions. The authors say that professional interpretation and test validation, comparable to a CLIA-certified lab, are necessary to ensure that DTC test results are not misapplied.
“We are not advocating the end of DTC testing, nor are we universally denouncing DTC genetic testing companies,” the authors write. “However, we feel that the interpretations must be accurate and reasonable, with adequate and freely available interpretation support for consumers and physicians.”
A male patient received a DTC genetic test (company unnamed) based on the standard HumanHap550 panel (Illumina) supplemented with a custom set of 25,000 additional single nucleotide polymorphisms selected by the company. His results report that for TPMT he has “one *3B mutation and one *3C mutation, a homozygous nonfunctional alleles pattern resulting in significant enzyme deficiency. A person with these mutations has an increased risk of toxicity when treated with thiopurine drugs at standard doses.”
The report did contain the disclaimer that “the information contained in this report should not be used to independently establish a thiopurine regimen, or abolish or adjust an existing course of treatment” and that “only a medical professional can determine whether a thiopurine drug is right for a particular patient.”
“In our opinion, these results need to be held to the same standards as clinical institutions’,” co-author Catherine Brownstein, from Boston Children’s Hospital, tells DTET. “Pharmacogenomics serves no other purpose than clinical. It is not entertainment.”
Members of the Boston Children’s Hospital Clinical Pharmacogenomics Service (CPS; which provides nonpediatric outpatient consults) questioned some general technical aspects of the finding and further questioned the probability of the results, given this was the third incidence of this specific *3B/*3C call in three, unrelated, ethnically diverse test recipients. CPS decided to genotype the patient’s family (parents, wife, and children) using Sanger sequencing in a CLIA-certified laboratory (Claritas Genomics; Cambridge, Mass.), which confirmed his *1/*3A status, demonstrating the DTC summary is “misleading,” the authors say.
“The most reasonable interpretation of the genotype was not presented clearly, and patients may not realize that they need interpretative support,” write the authors. “These tests should be held to the same standards as clinical institutions[’] because of the burden or risk for the prescriber. Repeating testing may not be possible with time [critical] dosing decisions.”
Shannon Manzi, a study co-author, tells DTET that retesting is needed in half of cases they see, particularly if the patient-reported test results are not able to be tracked down at another institution, if they were performed as part of a research protocol or not in a CLIA-certified laboratory, or sometimes if it is necessary in order for the patient to accept a different interpretation.
So what harm was done? While acknowledging that cases like this are likely not “widespread,” Brownstein tells DTETmisapplication of test results is “possible.” If the patient required 6-mercaptopurine treatment for his Crohn’s disease and the treating physician had based treatment on the *3B/*3C status in the report, “it would not be catastrophic,” but he would be prescribed a dose 10 percent of standard versus a dose reduced 30 percent to 70 percent with the *1/*3A genotype, the patient actually has, leading to potential disease progression, worsening of symptoms, or unnecessary discomfort.
However, they write, had the patient had leukemia, which is standardly treated with a thiopurine, and the DTC result was used to inform treatment (a scenario the authors call not likely, but possible) there could have been “serious consequences including progression of disease” from the “dramatic” dose reduction called for with the reported genotype.
“This data needs to be supported with adequate disclaimers, so that consumers can understand there are risks. Like any other test, DTC genetic testing is not immune from risks,” Brownstein says.
Takeaway: This case study provides the first evidence of potential harm resulting from misinterpretation of DTC genetic test results. Enhanced validation requirements may make DTC pharmacogenomic results more clinically relevant.