Choosing the right genetic testing for Friedreich's ataxia
Sub Subramony, MD, discusses the types of genetic testing that are most effective when diagnosing a potential Friedreich’s ataxia case, and the science behind them.
About Sub Subramony, MD
Sub Subramony, MD, is a board-certified neurologist and neuromuscular medicine specialist at the Norman Fixel Institute for Neurological Diseases at University of Florida Health. He also serves as a professor in the University of Florida Department of Neurology with a joint appointment in pediatrics. His area of focus is genetic neuromuscular diseases, including Friedreich’s ataxia.
Transcript
Friedreich’s ataxia, of course, is detected by a targeted approach to DNA analysis for the Friedreich’s mutation. Friedreich’s ataxia is caused by an unusual mutation, which is an expansion of a triplet-repeat GAA in the frataxin gene.
The reason I bring this up is the fact that this type of repeat expansion is not detected by commonly used sequencing methodology. Increasingly for detection of many genetic diseases, the DNA is subjected to a sequencing methodology using appropriate equipment.
And this kind of sequencing technology simply looks at all the molecules that make up your gene, make up the DNA of interest. But this technology is useful because it can actually assess a large number of genes, like a couple hundred genes, or the entire coding portion of the gene, which is called the exome sequencing.
But those kind of technologies will not detect Friedreich’s ataxia. You need a different technology, such as Southern blot and PCR.
So unless you specifically ask for Friedreich’s ataxia and you just go for a sequencing technology, thinking that, “I can try to look at a large number of genes with one test,” you’re gonna miss Friedreich’s ataxia.
Now, about 96 or 97% of patients with Friedreich’s ataxia have this repeated — repeat — expansion called the GAA expansion on both copies of the frataxin gene. That is the maternal and paternal copy. But in about 3-4%, only one copy is expanded and the other copy then has a conventional mutation, which can be detected by sequencing technology. So the trick here is, of course, if you have a patient that looks as if he or she has Friedreich’s ataxia and your test detects only one expanded allele, the other allele will have to be sequenced.
So basically, what you start out with is looking for the GAA expansion in both alleles. And then if that’s positive, you have your diagnosis. If only one allele is expanded and your patient looks as if he or she has Friedreich’s ataxia, the other allele is subjected to a sequencing methodology to look for a conventional mutation. And many of the laboratories that offer Friedreich’s testing automatically will do this for you.
David Lynch, MD, PhD, is the director of the Friedreich’s Ataxia Program at Children’s Hospital of Philadelphia.