CLOVES syndrome is different than most other genetic conditions in that it is not inherited. The gene changes that cause CLOVES syndrome in a person are not found in that person’s parents, siblings, or children. CLOVES syndrome is caused by changes (“mutations”) in a gene called PIK3CA and these changes are only present in some of a person’s cells. Just like people with CLOVES syndrome have some affected parts of their bodies and some unaffected parts of their bodies (for example, differences in just one leg but not the other, or skin changes in some places and not others), the PIK3CA mutations that cause CLOVES syndrome in a person are not present in all of that person’s cells. Scientists use different words to describe this, including “mosaicism,” and “segmental.” No matter what term is used, the important thing to know about CLOVES syndrome is that where and how you look for a causative mutation really matters. This graphic describes the genetics of CLOVES syndrome.
Genetic testing can be very helpful for people with CLOVES syndrome. Having a genetic test can help families and doctors understand treatment options that are already available. Treatments that are currently being tested or may become available in the future may also rely on a person’s genetic test results. Many healthcare providers are still unfamiliar with what mutations to test for and what samples are needed. Approximately half of the families involved in the CLOVES syndrome community have told us they had difficulty with genetic testing. The most common challenges are insurance coverage and getting the right kind of genetic test.
Genetic testing for CLOVES syndrome/PROS is more complicated than other kinds of genetic testing. It is important to be sure that the right sample is sent for testing and to understand how different genetic testing laboratories perform the test. You can read more about this in our FAQ. This site also has a good explanation of genetic testing.
What sample will be used for testing?
Almost all traditional genetic testing is done using blood or saliva samples. These are NOT the best samples to use for genetic testing for CLOVES syndrome. PIK3CA mutations that cause CLOVES syndrome just can’t be detected as well (or at all) in DNA that comes from these types of samples. No genetic test is perfect, but if a mutation is there, choosing a sample that comes from a part of the body that is clearly “affected” (showing signs of CLOVES syndrome) has the highest chance of finding it. For most people, this means having a skin biopsy done. Another option is to use tissue that might be available from a surgery that would ordinarily be thrown away. Having a skin biopsy (or sending surgical samples for genetic testing) takes more work for families and clinicians, and many parents don’t like the idea of having their child have a biopsy. Because genetic testing can be expensive and difficult to arrange, it’s often worth it to make sure that the best possible sample is used.
What laboratory will do the test?
Not all genetic testing laboratories (and there are LOTS of genetic testing labs!) test for CLOVES syndrome. Most offer CLOVES syndrome genetic testing as part of a “panel.” Many different genes that may cause similar conditions are tested at the same time. In some cases, the lab will only test specific mutations within the PIK3CA gene. Sometimes a person’s insurance will cover genetic testing at some laboratories and not others. It’s important for you and your doctor to understand the specific test that will be done. Exome sequencing, a very comprehensive and increasingly common test, especially for people with rare conditions, may not be the best test for people with CLOVES syndrome. It is very expensive and is often only done using a blood sample. Many families tell us that they had exome sequencing as their first diagnostic test. While CLOVES Syndrome Community does not endorse any of the following laboratories, they each offer tests that, when performed on the right DNA source or tissue sample, have a higher chance of finding a PIK3CA gene change compared to others.
When considering genetic testing, here are some “green lights” and “red flags” that can help you and your doctor decide on the best test for you/your child:
|Test||Green lights – signs of a more appropriate test for CLOVES syndrome||Red flags – signs of a less appropriate test for CLOVES syndrome|
|Sample type||fresh tissue, frozen tissue, DNA extracted from tissue||blood, saliva, DNA extracted from blood or saliva|
|Name of test||“Somatic overgrowth panel” includes “CLOVES syndrome” or “mosaic overgrowth” in name of test||Name of test seems to test for something else, e.g., “polydactyly panel”|
|Coverage||“deep sequencing” “ultra deep sequencing” “100x” “250x”||“20x coverage”|
|Detection language||“limit is 1%” “limit is 5%”||“variants present at <20% may not be reliably detected”|
How will the test be done?
There are lots of different ways genetic tests can be done. Finding the responsible mutation in a person with CLOVES syndrome is more of a “needle in a haystack” situation than many genetic tests because even in the “perfect” sample, the percentage of DNA with the mutation is lower than with other genetic conditions. Genetic tests designed to find the low-frequency mosaic mutations common in CLOVES syndrome are the best ones for people with CLOVES syndrome to get. It can be important to understand what the test’s lowest frequency is. Can the test find a mutation that may only be present in 1% of the DNA from the sample? 5%? 25%? Also, some genetic tests just look for specific mutations in specific genes, while others read through (“sequence”) whole genes. Having this information in advance can help families and providers pick the best test for the situation.
What will the results mean?
A “positive” result means that the test found a gene change or mutation in a gene that is known to be associated with CLOVES syndrome. Most people with CLOVES syndrome who get positive test results will have changes in the PIK3CA gene. A “negative” result can be complicated in a condition like CLOVES syndrome for a couple of reasons:
1) No genetic test is 100% perfect
2) A mutation may be present but not at a high enough level for the test to find. The lab may label any mutations found in less than 5% of the DNA in the sample as “negative.”
3) A mutation may not be present because the sample came from blood or saliva. This is common in CLOVES syndrome and why we suggest that DNA from biopsies is the best sample to send for genetic testing
4) A “true negative:” we do not know 100% of the genes that cause CLOVES syndrome so even a perfect test from a perfect sample will not give a positive result in a person whose mutation in a gene that has not been discovered yet.
Additional Resources for Genetics:
Visual created by the National Institutes of Health to help explain PIK3ca mutations and overgrowth. [March 20, 2017]
NIH Ongoing Research for PIK3CA mutations:
The National Institutes of Health does research testing of patients with all kinds of overgrowth. If you’d like to learn more, contact them at [email protected] or by phone at 301-435-6689. More information can be found here https://www.ncbi.nlm.nih.gov/gtr/tests/5534/
CLOVES Genetic Mutation Discovery (5/31/12)
Researchers at Boston Children’s Hospital identify a genetic cause for CLOVES