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Studies show for the first time how functional tests can clarify genetic false alarms and protect families from irreversible therapies and substantial costs
A positive newborn screening for spinal muscular atrophy (SMA) is currently considered a medical emergency. Without early treatment, severe disability or death in infancy are likely. However, research findings from Germany and Australia now show that in rare cases, a positive screening result can be a genetic false alarm. A collaborative research team led by 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) and Dr Jean Giacomotto from Griffith University’s Institute for Biomedicine and Glycomics, Brisbane, Australia, discovered that functional tests in a zebrafish model may enable fast and reliable clinical decision-making in cases of unclear genetic findings. The study ‘SMN1 variants identified by false positive SMA newborn screening tests: Therapeutic hurdles, and functional and epidemiological solutions’ was published in the American Journal of Human Genetics and another study, “Clinical relevance of zebrafish for gene variants testing. Proof-of-principle with SMN1/SMA”, in EMBO Molecular Medicine.
The scientists examined two newborns – a girl from Germany and a boy from Australia – in whom routine screening initially failed to detect the SMN1 gene. A missing SMN1 gene is the main genetic trigger of SMA. This diagnosis would normally result in immediate treatment, as it would be assumed that the child’s life is in danger. However, further genetic analysis revealed a surprising finding: both children carried rare SMN1 variants that had not been detected by the screening test. It remains unclear whether these variants cause the disease.
“For parents, such a diagnosis is extremely distressing. Within days, they are confronted with the prospect of a potentially fatal disease and the necessity of immediate, irreversible treatment,” says Wirth. “Our data show that in rare cases it is crucial to take a step back and clarify the functional significance of a variant.”
The researchers tested the specific SMN1 variants of the children in an established zebrafish model. Zebrafish embryos without a functional homologous SMN1 gene develop severe movement disorders within a few days and die prematurely. However, if a functional gene variant is introduced, the animals remain healthy.
Both SMN1 variants of the children turned out to be functional. The typical SMA symptoms did not occur in the animal model. “For the first time, we showed that every single, patient-specific gene variant can be functionally tested – and quickly enough to influence clinical decision,” says Dr Jean Giacomotto from Griffith University in Australia, who led the study in EMBO Molecular Medicine. Further functional analyses of the previously unknown SMN protein and epidemiological data analyses provided further evidence for the positive results from the zebrafish model.
In the case of the affected infants, after careful interdisciplinary consideration and in consultation with the parents, the treating medical teams decided against initiating SMA therapy. Today, both children are over two years old, developing normally in terms of motor skills, and showing no signs of neuromuscular disease. This not only spared the families considerable emotional stress, but also saved more than 2 million USD in therapy costs per child.
Both studies show that newborn screening can not only save lives, but also prevent unnecessary treatments if the results are interpreted correctly. According to the researchers, the increasing use of genomic screening is also leading to a rise in the number of genetic variants with unclear significance. Without functional classification, there was 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 regard zebrafish-based functional tests as a pioneering tool for quickly classifying genetic uncertainties not only in SMA, but also in many other rare diseases.
Professor Dr Brunhilde Wirth
Institute of Human Genetics, University of Cologne
brunhilde.wirth@uk-koeln.de
https://link.springer.com/article/10.1038/s44321-025-00355-8
https://doi.org/10.1016/j.ajhg.2026.01.012
https://uni-koeln.de/en/university/news/news/news-detail/false-alarm-in-newborn-...
zebrafish in the aquarium
Quelle: Griffith University
Copyright: Griffith University
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zebrafish in the aquarium
Quelle: Griffith University
Copyright: Griffith University
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