Research links genetic ‘spelling errors’ to FA disease severity
University of Oklahoma researcher gets $2.8 million grant for project
Genetic mutations causing Friedreich’s ataxia (FA) and influencing disease severity may be more complex than previously understood, according to research from the University of Oklahoma.
Sanjay Bidichandani, PhD, genetics section chief at the university’s medical college, used a new genetic sequencing technique to find “spelling errors” in the FXN gene that typical genetic analysis methods don’t capture, according to a university news story. People with these mutations seem to have a less severe form of FA, Bidichandani found.
The findings could lead to more accurate tests for diagnosing FA, as well as better tests for people who want to assess the risk of FA before they have children.
“Because the standard test performed by many clinical diagnostic labs does not detect the spelling errors, people may receive a false negative result for carrier testing,” Bidichandani said. “We have already discovered several families who’ve been told they’re not carriers, but when we do our specialized test, it turns out that they are carriers.”
Bidichandani received a $2.8 million grant from the U.S. Department of Defense to continue his research.
Understanding genetic variability
FXN mutations are the underlying cause of FA, which develops if a person inherits mutated copies of the gene from both biological parents. These mutations affect the protein frataxin, which is important in the process of cellular energy production. A lack of functional frataxin makes nerve and muscle cells, which have high energy requirements, particularly vulnerable, leading to FA symptoms like difficulty with coordination and muscle weakness.
The most common type of FXN mutation related to FA is called a GAA expansion. In a healthy person, a pattern of three DNA building blocks — one guanine (G) and two adenines (A) — is repeated five to 33 times in the FXN gene. In people with FA, repetitions can occur many more times, leading to disruptions in frataxin production.
Bidichandani’s findings indicate that other building block alterations may add nuance to GAA expansion mutations.
“We found different combinations of G’s and A’s that the original test could not detect,” he said. “It is a whole new level of genetic variability that was not being taken into account in the diagnosis and prognosis of Friedreich’s ataxia.”
A technique called long-read sequencing revealed these irregularities. Long-read sequencing can read longer strands of DNA without first breaking it into fragments. Compared with short-read sequencing, it offers higher accuracy for detecting structural or highly repetitive variants.
Based on current data, Bidichandani estimates that about 30% of people with FA have these spelling errors in their version of FXN. These individuals seem to have a milder form of the disease than those with typical GAA expansions, with slower disease progression.
“Our first goal with this new grant is to determine the real diversity of genotypes [genetic makeups] in people with Friedreich’s ataxia, and then to determine whether their condition is actually less severe,” Bidichandani said.
A difference in severity could complicate testing new therapies in a clinical trial setting. Without considering differences in genotype, it might be difficult to distinguish between someone responding to a medication and someone who has a milder form of the disease.
Bidichandani’s project received an impact award from the Defense Department’s Peer Reviewed Medical Research Program, which provides grants for research that may have immediate clinical impact.
A researcher at Children’s Hospital of Philadelphia is collaborating on the project, and shares a portion of the $2.8 million grant. Initial funding was provided by the Friedrich’s Ataxia Alliance.
“This is an exciting time for our research program,” Bidichandani said. “We believe our findings will have a beneficial impact on people with Friedreich’s ataxia and their families.”
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