A positive newborn screening for spinal muscular atrophy (SMA) is currently considered a medical emergency, prompting immediate investigation and potential treatment to prevent severe disability or even death. However, emerging research suggests that, in rare instances, a positive screening result can be a false alarm, stemming from genetic variants whose impact on health remains unclear. A collaborative study involving researchers in Germany and Australia has demonstrated that functional testing using a zebrafish model can help rapidly and reliably clarify these ambiguous genetic findings, potentially preventing unnecessary and costly treatments.
The findings, published in the American Journal of Human Genetics and EMBO Molecular Medicine, center around two infants – a girl from Germany and a boy from Australia – in whom initial newborn screening failed to detect the SMN1 gene. The absence of a functional SMN1 gene is the primary genetic cause of SMA. Typically, this finding would trigger immediate treatment, based on the assumption that the child’s life is at risk. However, more detailed genetic analysis revealed that both children carried rare variants of the SMN1 gene that were not identified by the standard screening test. The clinical significance of these variants was initially unknown.
“For parents, such a diagnosis is extremely distressing,” explains Professor Dr. Brunhilde Wirth, Director of the University of Cologne’s Institute of Human Genetics and Principal Investigator at the Center for Molecular Medicine Cologne (CMMC). “Within days, they are confronted with the prospect of a potentially fatal disease and the necessity of immediate, irreversible treatment. Our data show that in rare cases We see crucial to take a step back and clarify the functional significance of a variant.”
To determine whether these newly identified SMN1 variants were truly disease-causing, the researchers turned to zebrafish. Zebrafish embryos lacking a functional SMN1 gene exhibit severe movement disorders and premature death. The team tested the specific SMN1 variants from the two infants in a zebrafish model. If a functional gene variant is introduced into the zebrafish, the animals remain healthy and develop normally.
Remarkably, both SMN1 variants from the infants proved to be functional in the zebrafish model. The characteristic SMA symptoms did not develop in the zebrafish embryos carrying these variants. “For the first time, we showed that every single, patient-specific gene variant can be functionally tested—and quickly enough to influence clinical decisions,” says Dr. Jean Giacomotto from Griffith University in Australia, who led the study published in EMBO Molecular Medicine. Further analyses of the SMN protein and epidemiological data supported the positive results from the zebrafish model.
Based on these findings, and after careful consideration by an interdisciplinary medical team in consultation with the parents, the decision was made to withhold SMA therapy for both infants. Today, both children are over two years old and are developing normally, exhibiting no signs of neuromuscular disease. This approach not only alleviated significant emotional distress for the families but also avoided the substantial financial burden of SMA treatment, which can exceed 2 million USD per child.
These studies underscore that newborn screening, while life-saving in many cases, requires careful interpretation. The researchers emphasize that the increasing use of genomic screening is also leading to the identification of a growing number of genetic variants with uncertain significance. Without functional classification, there is a risk of overdiagnosis and unnecessary treatments.
“Early detection remains essential,” Wirth emphasizes. “But precision is just as important. Our goal is to give families security—the right kind of security.”
The researchers believe that zebrafish-based functional tests represent a promising tool for rapidly classifying genetic uncertainties, not only in SMA but also in a wide range of other rare diseases. This approach offers a pathway to more informed clinical decision-making and potentially avoids subjecting patients to treatments they do not need.
Publication details
Brunhilde Wirth et al, SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions, The American Journal of Human Genetics (2026). DOI: 10.1016/j.ajhg.2026.01.012
Brett W Stringer et al, Clinical relevance of zebrafish for gene variants testing. Proof-of-principle with SMN1/SMA, EMBO Molecular Medicine (2025). DOI: 10.1038/s44321-025-00355-8
