Clinical relevance of zebrafish for gene variants testing. Proof-of-principle with SMN1/SMA

Brett W Stringer; Yougang Zhang; Afsaneh Taghipour-Sheshdeh; Shuxiang Goh; Heike Kölbel; Michelle A Farrar; Brunhilde Wirth; Jean Giacomotto

doi:10.1038/s44321-025-00355-8

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Clinical relevance of zebrafish for gene variants testing. Proof-of-principle with SMN1/SMA

Journal article

Open access

Peer reviewed

Clinical relevance of zebrafish for gene variants testing. Proof-of-principle with SMN1/SMA

Brett W Stringer, Yougang Zhang, Afsaneh Taghipour-Sheshdeh, Shuxiang Goh, Heike Kölbel, Michelle A Farrar, Brunhilde Wirth and Jean Giacomotto

EMBO Molecular Medicine, Vol.18, pp.41-54

2026

DOI: https://doi.org/10.1038/s44321-025-00355-8

PMCID: PMC12808650

PMID: 41398093

Appears in Thompson Institute Research Collection

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Abstract

Functional Test

Diagnosis

Hypomorphic Variants

VUS Resolution

Motor Neuron Disease

Precision Medicine

Other Collaborations

Thompson Institute Special Collection

Spinal muscular atrophy (SMA) results from SMN1 gene loss-of-function (LOF), with disease severity directly linked to the level of remaining SMN protein. Nusinersen, risdiplam, and onasemnogene abeparvovec are revolutionary treatments but should ideally be implemented before clinical symptoms appear. Because of this, prenatal and newborn screenings are increasingly used to identify common SMN1 variants and patients requiring therapy. However, for novel variants, clinicians lack robust analytic tools to predict pathogenicity before irreversible damage occurs. To address this gap, we deployed a zebrafish model presenting smn1-LOF, exhibiting progressive motor defects and death by only six days of age. We evaluated two SMN1-variants of uncertain significance (VUS) identified in newborn infants awaiting definite diagnosis and treatment recommendations. We demonstrated that while known pathogenic variants did not change the disease course, wild-type SMN1 and both infants variants rescued SMA hallmarks in zebrafish, demonstrating the relevance of this approach for VUS-testing within a crucial timeframe for patients. Extending the assay to known SMN1-hypomorphs showed partial rescue, weaker than wild-type or VUS, demonstrating that this approach can also discriminate partial-LOF effects. Both VUS were resolved to be non-pathogenic, and the therapeutic costs of >US$2 million per child were avoided. Beyond SMA, this study provides robust proof-of-principle that the zebrafish represents a powerful translational tool for VUS-analysis, and that such approaches should be considered in clinical settings for supporting diagnosis and treatment decisions.

Details

Title: Clinical relevance of zebrafish for gene variants testing. Proof-of-principle with SMN1/SMA
Authors: Brett W Stringer - Griffith University
Yougang Zhang - Griffith University
Afsaneh Taghipour-Sheshdeh - Griffith University
Shuxiang Goh - UNSW Sydney
Heike Kölbel - Essen University Hospital
Michelle A Farrar - Sydney Children's Hospital
Brunhilde Wirth - University Hospital Cologne
Jean Giacomotto - University of the Sunshine Coast, Queensland, Thompson Institute
Publication details: EMBO Molecular Medicine, Vol.18, pp.41-54
Publisher: Wiley-Blackwell Publishing Ltd.
Date published: 2026
DOI: 10.1038/s44321-025-00355-8
ISSN: 1757-4684
PMID: 41398093; PMC12808650
Copyright note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.
Data Availability: This study includes no data deposited in external repositories. The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-025-00355-8.
Grants: ZebraClinics. From the identification of drugs against neurodegeneration to a better understanding of synaptic development and function., 1174145, National Health and Medical Research Council (Australia, Canberra) - NHMRC
Grant note: This study was funded by an Australian Functional Genomics Network Catalyst Grant #11501 to JG, BW & SG, and a Center for Molecular Medicine Cologne Grant (C18) grant to BW.
Organisation Unit: Thompson Institute
Language: English
Record Identifier: 991192142102621
Output Type: Journal article

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