Genetic technology has made rapid advances in recent years. We are nearing the era of the $1,000 genome, making genetic and genomic technology more affordable and accessible than ever before. We now have the capability to sequence the entire genome, all 3 billion (yes, billion with a b) base pairs, and identify more and more genetic changes or variants.
These advancements are tremendous and have provided answers for families who have been searching for years, and even generations, to identify the cause of the disorder in their family. With a diagnosis we have been able to point patients toward effective therapies, offer accurate risk assessments, and provide hope through clinical trials.
But as the technology is better able to find these genetic changes, we are coming across many novel, unreported changes in genes and are unsure what to do with them.
We all have genetic variation – just look around. This variation is responsible for much of the diversity among our species and helps create healthier offspring. Genetic variation is a good thing.
When the lab finds a genetic difference, something that is unexpected or different from the “normal” gene sequence, the question becomes…
What does it actually mean?
For example the typical sequence of AACTTTGA may be expected, but the patient’s results show AACTTTGC. Is this something benign like the difference between blue eyes and green eyes? Or does that single letter change cause a fundamental defect in the resulting protein leading to disease? After all, many genetic disorders, including sickle cell disease and achondroplasia, are due to a single letter change in the disease causing gene.
If it’s a change we have seen often in patients with similar findings or has been proven in the scientific literature to be disease causing, we have our answer. But what if the change we see in a patient sample is new to us and has not been reported before? The challenge for diagnosticians is what to do with those variations – how do we report it and what do we call it?
Thus we have coined the term ‘variant of uncertain significance,’ also known as a VOUS or VUS. VOUS has become a four-letter word in genetics, and unfortunately, they are common. As we look at the DNA sequence through single gene testing, panels of genes, or even whole exomes or genomes, we are occasionally going to find changes that we don’t know what to do with. It’s frustrating for laboratory geneticists and clinicians, and complicated and confusing for families.
Genetic counselors discuss the possibility of VOUS results with patients before testing is ordered, making the family aware in advance of all potential results and what they could mean. But that preparation still doesn’t make it much easier to disclose VOUS results to patients. “What do you mean you found something, but can’t explain it?” “A change is bad, right?”
So, how does the lab investigate these new changes?
One way is to look at the parents. If the change is new or ‘de novo’ in the patient, meaning that it is not present in either parent, we become more suspicious that it is significant.
Diagnosticians also research the scientific literature and various databases to see if the change has ever been reported before, and if so, did that patient have findings similar to our patient?
Other ways to evaluate the significance of a change include more study and analysis of the specific change including…
- What is the function of the gene that contains the variant?
- If that gene were disrupted, would we expect the features that we see in this patient?
- Is this variant in a part of the gene that is likely to disrupt its function?
- Does the variant alter the resulting protein structure or halt it altogether?
- There are numerous computer algorithms and methodologies that help answer these and other questions, and can predict whether a specific change is likely to be disease causing.
GGC’s Dr. Charles Schwartz has recently published a paper on a new technique that is helping to clear up some of these answers in a gene called KMT2D which causes Kabuki syndrome. Dr. Schwartz and his colleagues in Ontario were able to analyze this gene’s expression and through a new scoring system, could identify which VOUSs in that gene were actually causing the disorder. Research like Dr. Schwartz’s is happening around the globe and new methods such as this are providing clearer evidence of what many VOUSs actually mean.
We must, however, use caution in evaluating and interpreting all of the available evidence. It would be reckless to identify a benign change as disease-causing without firm and complete evidence – providing false answers and the potential for ineffective, or even harmful, procedures or treatments. It would be just as dangerous to call a harmful change as benign – offering false reassurance and potentially altering medical management incorrectly.
So for the time being, VOUSs aren’t going away. While laboratory technologies so far have outpaced our ability to understand these changes, a recent explosion in bioinformatics tools and research such as that Dr. Schwartz’s team is conducting, is bringing that understanding closer each day.
A VOUS today is not likely to stay a VOUS forever.