Mutations in the FXN gene — responsible for Friedreich’s ataxia (FA) — mainly come in the form of repeats of three DNA bases, GAA, at the start of the gene. Cases where one gene copy holds a repeat mutation and the other copy contains another kind of mutation account for only 2 percent to 4 percent of all patients. Particularly, mutations in the form of a deletion have been described as “exquisitely rare,” but a new study suggests that they might be more frequent than previously thought.
The study, titled “Friedreich ataxia is not only a GAA repeats expansion disorder: implications for molecular testing and counselling,“ describes a case of an FA patient with this particular combination of mutations. Among a group of suspected FA patients, the research team from the Polish Academy of Sciences found that most had two copies of the repeat mutation. They also identified one patient with one copy of the FXN gene holding the repeat mutations, with the other copy totally missing, according to the report published in the Journal of Applied Genetics.
By using molecular testing techniques, the team confirmed that all the coding regions of the gene were deleted. Researchers believe that if the frataxin protein is entirely missing, a fetus does not survive through to birth. Although most patients with FA have very low levels of frataxin, scientists have never come across a patient with no, at least partially functional, copy of the gene. The deletion of one entire gene copy has only been described in one patient previously.
Today’s routine genetic screening of FA focuses on the GAA repeats, and more detailed genetic testing is only performed when the repeat mutations cannot be confirmed. Often screening techniques are rather crude, confirming only the lack of extended GAA repeats in both gene copies.
When a lack of the repeat mutation is found in both gene copies, it could, of course, mean that the individual has two normal gene copies. The same result would, however, be observed if the patient has one repeat mutation and a deletion of the entire region normally holding the repeats in the other copy.
The authors maintain that in cases where FA patients show a number of characteristics, such as early onset, faster progression of neurological and heart symptoms, and more pronounced cardiomyopathy, extended genetic testing might be appropriate. These characteristics made the team suspect a deletion and opt for extended testing in this case. Knowledge of the genetic makeup, while holding no prognostic value, is important from a genetic counseling point of view, they argued.