SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions - PubMed
6 days ago
- #newborn screening
- #false positives
- #SMN1 variants
- Newborn screening (NBS) for spinal muscular atrophy (SMA) identifies bi-allelic SMN1 deletions but can miss rare sequence variants.
- Two newborns (P1 and P2) were falsely identified as lacking SMN1 due to 4-bp deletions in SMN1 exon 7, disrupting PCR assay primer-binding sites.
- Both variants (c.855_858delAGAA and c.861_864delAAGG) cause the same frameshift (p.Arg288AlafsTer5), predicted to be deleterious but with preserved exon 7 splicing.
- Functional studies showed markedly reduced SMN protein abundance but wild-type-like thermostability and full rescue of motor defects in zebrafish smn1 mutants.
- Population data (gnomAD) suggest ~800 European ancestry individuals may carry these variants in trans with an SMN1 deletion, yet none have SMA.
- Both children remained healthy at 24 months without therapy, avoiding >$4 million in treatment costs.
- Findings challenge the assumption that complete loss of full-length SMN invariably causes SMA, suggesting low levels of this novel SMN isoform can sustain normal motor development.