PUBLICATION
SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions
- Authors
- Wirth, B., Das, J., Kölbel, H., Goh, S., Farrar, M.A., Piano, V., Zetzsche, S., Fuhrmann, N., Becker, J., Karakaya, M., Zhang, Y., Cao, Y., Taghipour-Sheshdeh, A., Stringer, B.W., Giacomotto, J.
- ID
- ZDB-PUB-260214-7
- Date
- 2026
- Source
- American journal of human genetics 113: 627-635 (Journal)
- Registered Authors
- Giacomotto, Jean
- Keywords
- SMN1, SMN2, false positive genetic, functional studies, genetic epidemiology, newborn screening, spinal muscular atrophy, thermostability assay, variant interpretation, zebrafish model
- MeSH Terms
-
- Animals
- Australia/epidemiology
- Exons/genetics
- False Positive Reactions
- Female
- Germany/epidemiology
- Humans
- Infant, Newborn
- Male
- Muscular Atrophy, Spinal*/diagnosis
- Muscular Atrophy, Spinal*/epidemiology
- Muscular Atrophy, Spinal*/genetics
- Neonatal Screening*/methods
- Survival of Motor Neuron 1 Protein*/genetics
- Survival of Motor Neuron 2 Protein/genetics
- Zebrafish/genetics
- PubMed
- 41687605 Full text @ Am. J. Hum. Genet.
Citation
Wirth, B., Das, J., Kölbel, H., Goh, S., Farrar, M.A., Piano, V., Zetzsche, S., Fuhrmann, N., Becker, J., Karakaya, M., Zhang, Y., Cao, Y., Taghipour-Sheshdeh, A., Stringer, B.W., Giacomotto, J. (2026) SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions. American journal of human genetics. 113:627-635.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping