Clinical Testing for Genetic Mutations
Please print this webpage and this letter for your doctor when you request genetic testing. This will help explain the need for testing to your doctor and provide them with the information they need to justify testing to your insurance company. It will also direct them to laboratories that perform testing.
Genetic testing is most likely to identify mutations in individuals who have either multiple CCM lesions and/or a family history of CCM. Genetic testing is unlikely to identify mutations in individuals with sporadic CCM (single lesions with no family history). The cause of sporadic CCM remains unknown, but it is not believed to be due to inheritable mutations.
The standard strategy for genetic testing is to begin by sequencing the CCM1 gene. This is because mutations in the CCM1 gene are most common (seen in at least 53% of all CCM families). If no mutation is identified, CCM2 then CCM3 will be sequenced. CCM2 gene mutations account for at least 15%, and CCM3 mutations account for roughly 10%, of familial CCM cases. Individuals with Mexican heritage may chose to specifically test for the “Common Hispanic Mutation’ on CCM1 before sequencing the entire gene.
If sequencing of all three genes is completed and no mutation identified, deletion testing is the next step. Deletions of whole or partial genes cannot be indentified by standard sequencing and requires specialized testing.
Clinical vs Research Testing
Testing for genetic mutations may be for research or clinical purposes. Because of its strict regulation, only clinical testing can be used to make a diagnosis of a genetic mutation. Research testing (that which you get when you enroll in a study) must be verified by a clinical test before it is considered to be a formal diagnosis. For this reason specific research results are not typically given to the study participant. Instead, he or she maybe recommended to have clinical testing done.
Where to have testing
At this time, there are four laboratories in the USA that are approved to perform clinical testing of the CCM1, CCM2, and CCM3 genes. These are PreventionGenetics, Gene Dx, Athena Diagnostics and ARUP Laboratories; all are for-profit laboratories.
The information below describes the tests that are offered at the time of this posting. The information that your doctor or genetic counselor will need to begin the testing process can be found in the links below. These sites provide the specimen and shipping requirements as well as the CPT codes that can be used to bill insurance. Many insurance carriers will cover diagnostic genetic testing.
All four of these companies offer both sequencing and deletion testing, require a blood sample, and have a result turn around time between 3 and 8 weeks. Depending on your healthcare and insurance providers, you may or may not be able to choose which company does your testing.
What to know before you test
Before beginning clinical genetic testing, there are several things to know.
First, genetic testing by sequencing the gene can only rule in a mutation; it cannot rule out one. This means that a negative result does not necessarily mean that a genetic mutation does not exist. There are two reasons for this. First, this is because there are ways that a gene can mutate that are not picked up by sequencing – follow up testing would be performed if this were suspected. Follow up may likely include deletion testing because whole-gene and partial gene deletions are not detected by standard sequencing techniques.
Second, there is evidence that not all of the genes that can cause hereditary CCM have been discovered at this time – there may be a CCM4 gene that has yet to be discovered.
That said, if you choose to have genetic testing and a genetic mutation is identified, this can make it very affordable for your family to be screened for the mutation. Rather than going through an MRI, other family members can submit blood, or in some cases simple cheek swabs, for “CCM Known Mutation Detection.”
Genetic testing can yield potentially upsetting results. Please make certain that you have the necessary support –a genetic counselor or a very knowledgeable and compassionate doctor – before beginning this process.
GeneReviews eBook; Cerebral Cavernous Malformation, Familial http://www.ncbi.nlm.nih.gov/books/NBK1293/