Test using zebrafish model helps doctors rule out SMA in 2 infants
Tiny fish may help clinicians clarify results of genetic testing: Study
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- Genetic testing for SMA can show uncertain results, creating dilemmas for families over whether to start early, costly treatment.
- A rapid zebrafish model test clarified the impact of genetic variants for two babies in Australia.
- Researchers say this method could provide timely, affordable clarification of genetic testing results.
A rapid test using zebrafish was able to show that two children identified by genetic testing as possibly having spinal muscular atrophy (SMA) did not actually have the progressive disease, according to a new study.
This finding, the researchers say, shows how these tiny fish — which have long been used as a research model to study diseases and their development — could help clinicians tailor personalized care as genetic testing becomes more commonplace.
“This research provides the clearest demonstration to date that zebrafish can play a decisive role in clinical variant interpretation, particularly in newborns flagged through expanding genomic screening programs,” Jean Giacomotto, PhD, senior author of the study at Griffith University in Australia, said in a university news story.
For these two children, the results of the zebrafish testing allowed their families to delay, and ultimately not move forward with, costly treatment that the researchers now say wasn’t needed.
The study, “Clinical relevance of zebrafish for gene variants testing. Proof-of-principle with SMN1/SMA,” was published in the journal EMBO Molecular Medicine.
SMA is a genetic disorder caused mainly by mutations in the gene SMN1. SMA-causing mutations render this gene dysfunctional, which results in the loss of nerve cells that control movement. The most common form of SMA, type 1, is usually fatal in infancy without treatment. Patients with less common, milder forms of the disease tend to live longer but still typically develop substantial motor disability without treatment.
SMA treatments work best when given as early as possible
Several disease-modifying therapies for SMA are available for patients. All of these treatments have been proven to help prevent SMA progression, but have limited ability to reverse damage that’s already occurred. Thus, these treatments are most effective when given as early as possible.
Given this, there’s been an increasing push in recent years to expand newborn screening, which aims to systematically test all babies for SMA so that those with the disease can be given treatment as soon as possible.
“Without treatment, SMA is typically fatal, and while highly effective therapies now exist, they can exceed US$2 million per child per year and must be initiated before symptoms appear,” Giacomotto said. The scientist noted that, if treatment is delayed, “the child will have already experienced irreversible degenerative damage, leading to lifelong problems and possibly death within the first years of life.”
One way to screen for SMA is through genomic sequencing, which determines the sequence of the SMN1 gene. However, interpreting results from these tests can be tricky. In some cases, a change in the SMN1 genetic code is an SMA-causing mutation. But it’s also possible for there to be variants in the gene that don’t cause SMA and are simply a consequence of the vast variability in human genetics.
When clinicians encounter a variation that they’ve never seen before, they often don’t know if it’s a disease-causing mutation or a harmless variant, and this presents a conundrum for families: Is it better to wait, potentially allowing a suspected disease to irreversibly progress, or give treatment immediately and endure unnecessary medical risks and costs if the variant isn’t disease causing?
Using the zebrafish model for testing took 18 working days
This was the case for two babies who underwent genetic sequencing and were found to have SMN1 gene variations that had not previously been reported. Neither of the babies had obvious symptoms, but the families weren’t sure if they needed to start treatment or not.
To help guide the families, the scientists ran tests in zebrafish. The team had previously developed a zebrafish model lacking any healthy SMN1 protein. These fish developed severe disease similar to SMA type 1. Specifically, they displayed growth defects within a few days of birth, and none survived longer than a week.
Essentially, the researchers engineered these zebrafish so they would have messenger RNA (mRNA) from either a healthy SMN1 gene or one of the newly identified variants (861VUS and 855VUS). mRNA is an intermediate molecule made from the genetic information in DNA that’s used to produce proteins.
The team found that all of these mRNAs restored the motor function and survival of the fish. “These results robustly demonstrate that both the 861VUS and 855VUS produce functional SMN protein,” the investigators wrote.
Additional tests using SMN1 mutations that cause milder forms of SMA also slightly improved survival, but not as well as the healthy version of the gene or the novel variants.
Following this testing, the researchers concluded that these novel variants seem to function just as well as the most common version of the SMN1 gene.
Importantly, the team noted, assessing these SMN1 variants took 18 working days — meaning the families had an answer within a timeframe that could have allowed for early initiation of treatment had it been needed.
Babies showed no SMA symptoms at 1 year
According to the researchers, the babies were approximately 6 months and “still asymptomatic” by the time the experiments were finished.
“After review and consultation with clinicians, a decision was made not to implement treatment and wait until the patients were 12 months old to write this manuscript, at which time both infants remained asymptomatic, exhibiting normal motor, neurological and electrophysiology examination,” the investigators wrote. The team added that “both patients achieved all motor milestones at expected timepoints.”
With genomic sequencing rising worldwide, clinicians are encountering more and more uncertain variants. This tiny fish offers a fast and affordable way to help resolve these cases and reduce distress for families.
Going forward, Giacomotto said this fish-based platform may be a useful way to test SMN1 mutations whose clinical implications are unclear.
“With genomic sequencing rising worldwide, clinicians are encountering more and more uncertain variants. This tiny fish offers a fast and affordable way to help resolve these cases and reduce distress for families,” Giacomotto said.
