As scientists continue to link inheritable diseases to specific genes, genetic tests are becoming a standard tool in the diagnosis of neuromuscular diseases. Many are available on a fee-for-service basis from commercial or university labs, and others are available (sometimes free of charge) from research laboratories studying certain diseases.
Because genetic tests look for genetic errors that are known to cause certain inheritable diseases, they can help provide a definitive diagnosis. Perhaps more importantly, they can detect an inheritable disease in a family even in the absence of any symptoms or family history, so they can help in early care and planning for the disease.
But while genetic tests have the potential to do these things, sometimes they seem to provide no information or even conflicting information. For example, patients sometimes receive a nearly certain diagnosis based on the results of other tests, but then the genetic test gives a negative result. How sensitive are genetic tests, and what factors influence their results? Knowing the answers can help you avoid confusion and frustration.
It's important to remember that a gene is a set of instructions for making a protein. Those instructions are written in the chemical language of DNA (deoxyribonucleic acid), which is based on an alphabet of just four "letters," called nucleotides (C, T, G and A). Some nucleotides — located in "regulatory" regions of a gene — spell out commands for making the protein, but don't contribute directly to the protein. Others in the "expressed" regions, or exons, of a gene spell out the protein.
An error, or mutation, anywhere in a gene can alter the quantity or quality of protein produced, interfering with vital events within the body's cells. Some mutations are deletions or duplications, which remove or add long strings of nucleotides, causing a potentially harmful loss or gain of protein. Other mutations, called trinucleotide repeat expansions, are long strings of a repeated three-nucleotide phrase that can turn into a tangled mess. Others are point mutations, which change, add or remove individual nucleotides, sometimes leading to disastrously altered proteins.
Genetic testing is done by drawing a blood sample, and extracting DNA from white blood cells. Genetic tests can accurately identify disease-causing mutations, but their use and sensitivity are limited by our current knowledge about inheritable diseases. Because genetic tests are designed to look for mutations in specific genes, they aren't available for inheritable diseases where the defective gene is unknown.
For a couple of reasons, there's a good chance a genetic test will yield a false negative (failure to detect a disease-causing mutation). First, diseases like Charcot-Marie-Tooth disease (CMT) can arise from mutations in one of many different genes; some of these genes are unknown and therefore beyond the limits of detection. Second, commercially available genetic tests are designed to detect the most common mutations that cause a disease; therefore, these tests will miss rare disease-causing mutations.
For example, diseases like hypokalemic periodic paralysis are associated with common point mutations. Therefore, genetic tests for these diseases are usually designed to detect those point mutations, and can miss other types of mutations. Diseases like Duchenne or Becker muscular dystrophy (DMD/BMD), on the other hand, are typically caused by genetic deletions or duplications. Therefore, tests for diseases like DMD/BMD are good at finding deletions and duplications, but poor at finding point mutations.
There's also the possibility that a mutation revealed by a genetic test might not be recognized as a disease-causing mutation. For instance, some single nucleotide changes have clear functional consequences, but many are "silent" with no obvious effects on health. Even detection of a trinucleotide repeat expansion can be ambiguous, since relatively short expansions are sometimes harmless.
Another shortcoming of most genetic tests is that they look for mutations in the expressed regions of a gene, but ignore the regulatory regions. So, even though a mutation in a regulatory region can cause detrimental loss of a protein, such a mutation might not show up in many genetic tests.
Using genetic testing to detect carriers — people who have a mutation, but don't develop the disease — is especially tricky. Typically, such a person has inherited a mutant gene from one parent and a normal gene from another parent. However, a carrier might also harbor a mutation that's only found in germ cells (the sperm or eggs), and only in some of those. In this case, a genetic test (done on white blood cells) will miss the mutation.
These limitations can severely restrict the sensitivity of genetic testing. For example, it's estimated that genetic tests miss about 30 percent of the mutations in the dystrophin gene that cause DMD/BMD. (The situation is improving: Scientists have recently developed a fast, accurate method for detecting point mutations in DMD, but it's not yet commercially available.)
This high risk of false negatives doesn't mean that genetic tests are useless. In someone who has a neuromuscular disease, a positive result can distinguish among different diseases with similar symptoms. In someone with a family history of a disease, a positive result can tell if that person will develop the disease or pass it on to children.
A negative result might be a true negative or might mean that the genetic test wasn't sensitive enough to find the disease-causing mutation. The results of other diagnostic tests such as a muscle biopsy can help distinguish these two possibilities.
In general, if you have a genetic test done, you should be wary of drawing any strong conclusions from a negative result. If you have questions about a genetic test result, a genetic counselor through your MDA clinic is a good source for answers.
For a complete guide to available genetic tests and testing centers, searchable by disease, check out the Web site www.genetests.org or call (206) 527-5742. (Registration is required, but free.)
"Simply Stated" is a Quest column designed to explain some terms and basic facts about neuromuscular disease.