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Screening vs. Diagnostics: Can Preventive Genomics Clinics Help Healthy Patients?

By Emily Quian

Preventive health clinics at large academic medical centers are one of many changes that allow individuals to be in the driver’s seat of their own health care. While many of these programs have existed for quite some time under the guise of an “executive health clinic” or “executive health services,” the introduction of preventive genetic testing in these clinics is relatively new. Furthermore, there are also clinics dedicated to the specialized area of proactive genomic screening opening up to the general public (who can afford self-pay appointments and testing). Test offerings at these clinics often comprise a suite of screening genetic tests, which differ largely from diagnostic tests.

Some genetic testing laboratories have specifically designed screening tests that can uncover medically actionable findings in ostensibly healthy individuals. For screening genetic tests, the variability in the range of technologies used (wet lab and bioinformatics), gene-diseases covered, genetic variant interpretations, and their reporting thresholds is considerable. For diagnostic genetic tests, the differences often lie in the technology used in the wet lab and the genes included in analysis (there may be subtle differences in bioinformatics). The variant interpretation frameworks are largely standardized (although most laboratories have added their own tweaks and flairs to the guidelines) and the reporting thresholds typically do not vary largely between diagnostic genetic tests.

Because of the discrepancies in the designs of genetic screening tests, clinicians offering this testing must now consider test elements that were stable before. For example, genetic variants associated with monogenic disorders (also known as Mendelian disorders) are classified in the following manner – with a quick explanation in layman’s terms:

  1. Pathogenic: Nearly 100% sure this variant is associated with the disease, not to be confused with penetrance which is the concept of whether or not one then goes on to develop the disease;
  2. Likely Pathogenic: Less confident than the above, but pretty sure it is associated with the disease;
  3. Variant of Uncertain Significance (VUS/VOUS): Ranges from “I think it might be related but I’m not sure” to “I have no idea what this variant means,” but could also mean “I’m seeing conflicting reports which brings us back to – I have no idea what this variant means;”
  4. Likely Benign: Pretty sure it isn’t linked to the disease;
  5. Benign: Nearly 100% sure it isn’t linked to the disease.

Nearly all diagnostic genetic tests will report variants classified as Pathogenic, Likely Pathogenic, and VUS/VOUS. Screening tests may only report Pathogenic, perhaps both Likely Pathogenic and Pathogenic, have different conditions for reporting VUS/VOUS, and/or include other types of genetic findings as well (low risk variants, polygenic risk scores, traits, nutrigenomics, etc.). I’m not going to go into the nuances of bioinformatics filtering here, but I’ll just say that every lab has its own specially built pipeline that “detects” variants. Because each laboratory has designed their own, clinicians will also need to understand the limitations of the laboratory’s custom pipeline. This is especially important for understanding and interpreting residual risk for a patient.

Now what about the tests that don’t require clinician guidance before ordering a test? Many of these screening tests are available direct-to-consumer (DTC), and others simply require a clinician’s signature to process a sample. From working at a laboratory that performs the latter, I can confidently say that there is a population of patients that would have benefited significantly from interaction with an educated clinician before ordering a screening genetic test.

Many individuals pursuing genetic testing have ailments that they are seeking a genetic diagnosis for, which is misaligned with the screening test’s design. These individuals were either not referred to genetics and decided to take their health care into their own hands, or had complex symptoms that are typically unable to be diagnosed by genetics. For example, adult-onset autoimmune conditions are notoriously difficult as they are often multifactorial in nature and not due to monogenic causes, which means that genetic testing is often not helpful. In both situations, the screening genetic test is inappropriate, and should have been addressed by the ordering clinician. The end result is often a disgruntled patient who has spent a significant amount of time and money on a test unable to produce the wanted results.

Upon receiving results, many patients also inquire about dietary tolerances, irritable bowel syndrome, homocysteine, methylation, or vitamin deficiencies. These topics are often not discussed by genetics professionals, which brings me to my next point: Are genetic professionals ready to engage consumers and guide them through this realm?

The short answer is yes, genetic professionals (in particular genetic counselors), are trained to be able to navigate these concerns and explain that genetic testing is unlikely to uncover an etiology for multifactorial conditions. Another concept that is conveyed to patients during clinic visits is the ever-changing field on genetics. With the rapid expansion of technology, the associated medical data used to drive guidelines has evolved as well.

For example, in 1998 a journal article was published stating that the lifetime risk of colon cancer caused by a pathogenic variant, previously referred to as mutations, in the MLH1 gene known to cause Lynch Syndrome (an inherited cancer predisposition) is up to ~84% if untreated. If we fast forward to 2017, National Comprehensive Cancer Network (NCCN) guidelines had quoted lifetime risk of colon cancer due to MLH1 as ~52-82%. In today’s NCCN guidelines (v2.2019), the lifetime risk for colon cancer Is now quoted as ~46-49%. As more “healthy” individuals get tested and more families are uncovered with these pathogenic variants, the lifetime risk estimates may continue to decrease. This will likely happen for variants across many genes, but not all.

In true fashion as clinicians at the cutting edge of science, genetic professionals should continue to inform patients that there will always be a bit of uncertainty surrounding these findings (yes, even the pathogenic ones), particularly as we interpret results in this new setting. I also encourage clinicians to begin considering other facets of test design as we begin to utilize proactive genetic screening tests.

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