What to do When the Last Genetic Tests Didn’t Find the Cause
Receiving a diagnosis from genetic testing (in other words, finding the specific change in a person’s DNA that causes their symptoms) can be a major milestone. However, there may be barriers to receiving a genetic diagnosis, from navigating insurance to ordering the correct test to accessing genetics professionals. Because of this, people in the process are often said to be on a “diagnostic odyssey.” But when the all tests have been run, the DNA analyzed in different ways, the data crunched, and the results returned—all without a diagnosis—what options are left?
For many, this is the end of their journey. More genetic tests or a research study may be available, but these are generally too expensive or limited in their ability to find a diagnosis. But there is another route to a diagnosis that is gaining popularity and may have a better chance of finding a diagnosis: reanalyzing past genetic data.
Reanalysis: (Re)reading the Data
Certain genetic tests like exome or whole genome sequencing are perfect for reanalysis. They yield vast amounts of data, but much of it is not able to be analyzed on the first round. Reanalyzing a person’s genetic data goes back to look at this same information—it’s like going back to an old mine to search for gold deposits, but with more knowledge about the land and, sometimes, better tools.
Some reasons that a lab may not analyze all data from the initial exome or genome sequencing test are:
that there are thousands of genes are still not linked to a condition and may not be analyzed because they won’t lead to a diagnosis;
knowledge about which genetic changes are important is always being updated as time goes by.
So, it’s possible a gene is not originally analyzed, or a certain genetic change is thought to be benign. But when doing an updated analysis, more information may be available that simply wasn’t known at the time of the original test.
It’s important to know that not all tests and genetic data can be reanalyzed, which may depend on the laboratory’s policy or the specific test capabilities. Some tests with limited opportunities for reanalysis include karyotypes, fragile X syndrome testing, gene panels, and pharmacogenomic results. If you or a family member has had exome or genome sequencing, then reanalyzing the data can be a great option to find a diagnosis. So, when should you or a family member consider asking your doctor or the laboratory to review the original genetic data?
When to think about reanalysis
There are two times reanalysis often makes the most sense. The first scenario is if the person has new or worsening symptoms. The second scenario involves the length of time since the original test was done.
A person has new or worsening symptoms. When this happens, the person’s symptoms may be due to an undiagnosed genetic condition that caused their original symptoms. For example, if a person has an autism diagnosis, but now they are having seizures, too. This is helpful information for the laboratory that did the original genetic testing. With this new information the laboratory can do an updated analysis and search for genetic changes in new genes linked to the symptoms.
Time has passed since the original testing. As time passes, more research is published about how genetic changes cause conditions. Recent studies show that up to 3 out of 20 people (about 5-15%) will receive a diagnosis after reanalysis1, 2. Some studies suggest waiting 6-12 months for people with learning difficulties/intellectual disability or seizure2 while others suggest waiting longer, like 1-3 years1. The more time has passed, the greater the chance to find a diagnosis.
The Reanalysis Process
One option to start the process is to discuss it with the doctor who ordered the original testing. Many labs now offer reanalysis, but policies and pricing will vary. We suggest contacting the laboratory where testing was performed.
Lastly, who should do the reanalysis? In general, it is best to have the original laboratory reanalyze the data instead of requesting the raw data for an outside laboratory or third party. Data can be tricky to analyze, and the original laboratory is already familiar with the test and any nuances within the data. A person looking at the data for the first time may think they have found a diagnosis when the genetic changes is really a known error in the original testing (which is why it was not reported in the first place). Professionals who analyze exome or genome data should have board certification from the American Board of Medical Genetics and Genomics.
Reanalysis of genetic testing data is an important option for people still searching for a diagnosis.
If you or a family member have new symptoms, worsening symptoms, or at least 6-12 months have passed, studies suggest up to 3 out of 20 people (about 5-15%) will receive a diagnosis after reviewing previous exome or genome sequencing data.
Discuss reanalysis with the doctor who ordered the original exome or whole genome test or call the laboratory who performed it and ask to speak with a genetic counselor.