SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions

Brunhilde Wirth; Joyosmita Das; Heike Kölbel; Shuxiang Goh; Michelle A. Farrar; Valentina Piano; Sebastian Zetzsche; Nico Fuhrmann; Jutta Becker; Mert Karakaya; Yougang Zhang; Yuqing Cao; Afsaneh Taghipour-Sheshdeh; Brett W. Stringer; Jean Giacomotto

doi:10.1016/j.ajhg.2026.01.012

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SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions

Journal article

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SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions

Brunhilde Wirth, Joyosmita Das, Heike Kölbel, Shuxiang Goh, Michelle A. Farrar, Valentina Piano, Sebastian Zetzsche, Nico Fuhrmann, Jutta Becker, Mert Karakaya, …

American Journal of Human Genetics, Vol.113(3), pp.627-635

2026

DOI: https://doi.org/10.1016/j.ajhg.2026.01.012

PMID: 41687605

Appears in Thompson Institute Research Collection

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Abstract

false positive genetic

functional studies

genetic epidemiology

newborn screening

SMN1

SMN2

spinal muscular atrophy

thermostability assay

variant interpretation

zebrafish model

Thompson Institute Special Collection

Other Collaborations

Newborn screening (NBS) for spinal muscular atrophy (SMA) enables rapid diagnosis and pre-symptomatic treatment of infants with bi-allelic SMN1 deletions. Standard PCR-based assays detect ∼95% of cases by identifying the absence of SMN1 exon 7; however, rare sequence variants can escape detection. We describe two newborns (in Germany and Australia) identified by NBS as lacking SMN1 but subsequently shown to carry a single SMN1 copy—with no SMN2 in P1 and one SMN2 copy in P2. Gene-specific long-range PCR and Sanger sequencing revealed two distinct 4-bp deletions in SMN1 exon 7 (c.855_858delAGAA [p.Arg288AlafsTer5] in P1 and c.861_864delAAGG [p.Arg288AlafsTer5] in P2). Both variants disrupt the reverse primer-binding site used in NBS assays and cause the same frameshift p.Arg288AlafsTer5, predicted to be deleterious. A plethora of assays demonstrated preserved exon 7 splicing, markedly reduced SMN protein abundance, and wild-type-like protein thermostability. In vivo, expression of the p.Arg288AlafsTer5 protein in zebrafish fully rescued the progressive motor and survival defects of smn1-deficient mutants. These findings raise the possibility that this novel SMN isoform has enhanced functional efficiency relative to the wild type. Population data (gnomAD) suggest that ∼800 individuals of European ancestry may carry these variants in trans with an SMN1 deletion, yet none have been reported with SMA. Based on our data, no therapy was initiated. Both children remain healthy at 24 months of age, avoiding >US$4 million in potential treatment costs. These findings challenge the assumption that complete loss of full-length SMN invariably causes SMA and suggest that very low levels of this novel SMN isoform can sustain normal motor development.

Details

Title: SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions
Authors: Brunhilde Wirth (Corresponding Author) - University of Cologne
Joyosmita Das - Griffith University
Heike Kölbel - Essen University Hospital
Shuxiang Goh - UNSW Sydney
Michelle A. Farrar - Sydney Children's Hospital
Valentina Piano - University of Cologne
Sebastian Zetzsche - University of Cologne
Nico Fuhrmann - University of Cologne
Jutta Becker - University of Cologne
Mert Karakaya - University of Cologne
Yougang Zhang - Griffith University
Yuqing Cao - Griffith University
Afsaneh Taghipour-Sheshdeh - Griffith University
Brett W. Stringer - Griffith University
Jean Giacomotto - University of the Sunshine Coast
Publication details: American Journal of Human Genetics, Vol.113(3), pp.627-635
Publisher: Cell Press
Date published: 2026
DOI: 10.1016/j.ajhg.2026.01.012
ISSN: 1537-6605
PMID: 41687605
Copyright note: © 2026 The Authors. Published by Elsevier Inc. on behalf of American Society of Human Genetics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Data Availability: Data generated or analyzed during this study are included in the published article and the corresponding supplemental information. Zebrafish resources used in this study include the previously described smn1Y262stop mutant line and a newly generated transgenic line, Tg(UBI-mKate2-SMN1-861VUS). These lines are not deposited in public repositories but are available from Dr. J. Giacomotto upon reasonable request, in accordance with institutional and ethical regulations.
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 work was funded as follows: Australian Functional Genomics Network Catalyst Grant #11501 to J.G., S.G., and B.W.; a Center for Molecular Medicine Cologne (CMMC) grant to BW (C18); The Australian Functional Genomics Network is funded by the Medical Research Future Fund (funding ID MRF2007498) and administered by the Murdoch Children’s Research Institute.
Organisation Unit: Thompson Institute
Language: English
Record Identifier: 991214273602621
Output Type: Journal article

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