290: SMN1 p.Arg288AlafsTer5 exon 7 deletions evade PCR newborn screening yet yield functional SMN isoform

Wirth B et al., The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.012 - Two SMN1 exon 7 4-bp deletions (p.Arg288AlafsTer5) evade standard PCR newborn screening but produce a low-abundance, thermostable SMN protein that functionally rescues smn1-deficient zebrafish and averted therapy. Key terms: SMN1, spinal muscular atrophy, newborn screening, p.Arg288AlafsTer5, zebrafish rescue.

Study Highlights:
In two clinically healthy newborns flagged as lacking SMN1 by PCR-based NBS, long-range SMN1-specific PCR, Sanger sequencing, MLPA and ddPCR identified distinct 4-bp exon 7 deletions producing the same frameshift p.Arg288AlafsTer5. Cellular assays showed preserved exon 7 splicing, markedly reduced SMN protein abundance, and unchanged protein thermostability, while AlphaFold3 predicted only mild C-terminal structural alteration. Functional complementation in smn1-deficient zebrafish—using both mRNA injection and a stable Tg(UBI-mKate_SMN1-861VUS) transgene—fully rescued morphology, motor behavior, and survival. Population gnomAD analysis indicates these variants are rare but present in Europeans at a carrier frequency that predicts hundreds of compound heterozygotes without reported SMA, informing diagnostic sequencing and avoidance of unnecessary therapy.

Conclusion:
Integrated genetic, functional, structural, and population-level evidence supports likely non-pathogenic reclassification of the SMN1 c.855_858delAGAA and c.861_864delAAGG alleles and shows that very low levels of the altered SMN protein can preserve normal motor development.

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

First author:
Wirth B

Journal:
The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.012

DOI:
10.1016/j.ajhg.2026.01.012

Reference:
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., et al. SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions. The American Journal of Human Genetics. 2026 Mar 5;113:1–9. https://doi.org/10.1016/j.ajhg.2026.01.012

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the two SMN1 exon 7 4-bp deletions, their molecular consequences, splicing, protein abundance and thermostability, in vivo zebrafish rescue, and population-genetics data with implications for clinical practice.
- transcript topics: Identification of two SMN1 exon 7 4-bp deletions; Molecular confirmation and variant characterization; SMN1 exon 7 splicing preservation; SMN protein abundance and thermostability assessments; Zebrafish functional rescue experiments; Population genetics (gnomAD) data and carrier frequencies

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Two SMN1 exon 7 4-bp deletions (c.855_858delAGAA and c.861_864delAAGG) produce p.Arg288AlafsTer5
- Deletions disrupt the NBS primer-binding site, explaining initial SMN1 signal loss in screening
- Exon 7 splicing is preserved; SMN1 transcripts are full-length with no exon 7 skipping
- SMN protein abundance is markedly reduced in carriers
- Mutant SMN1 proteins are thermostable and structurally similar to WT
- In vivo zebrafish experiments show functional rescue by SMN1-855VUS and SMN1-861VUS

QC result: Pass.