Peer-reviewed article
Analytical Study Showing a False-Negative Limitation of Deletion-Based Newborn Screening for Spinal Muscular Atrophy Using a Compound Heterozygous <i>SMN1</i> Control.
Abe Y, Suzuki-Muromoto S, Kosuga M, Isayama T, Tajima G et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This analytical study evaluates a newborn screening test for spinal muscular atrophy (SMA), a genetic disorder affecting children. The researchers tested blood samples from newborns and patients with confirmed SMA to see how well the screening assay worked. The study found that while the test correctly identified patients with the most common form of SMA (homozygous deletion), it missed patients with a different genetic variant (compound heterozygous), showing a significant limitation of the current screening approach.
Key points
- The deletion-based SMA screening assay accurately detected homozygous SMN1 deletion in two SMA controls with no detectable amplification
- A patient with compound heterozygous SMN1 variants showed SMN1 copy numbers (7330 copies/µL) more than tenfold above the screening cutoff of 668 copies/µL
- The compound heterozygous SMA patient had a negative screening result at birth despite subsequently developing genetically confirmed SMA
- All 21 newborn participants were classified as screening-negative with SMN1 copy numbers above the cutoff
- Deletion-based SMA newborn screening has an inherent false-negative limitation that does not completely exclude SMA diagnosis
Limitations
This is an analytical laboratory study with a very small sample size (21 newborns, 3 SMA controls) and does not evaluate clinical outcomes or the effectiveness of early intervention. The findings are limited to technical performance of one specific screening assay and do not address population-level screening impact or long-term health benefits.
Abstract
Newborn screening (NBS) facilitates the presymptomatic diagnosis and early treatment of spinal muscular atrophy (SMA). An analytical study was conducted to evaluate the performance and limitations of a real-time polymerase chain reaction-based SMA-NBS assay. Dried blood spot specimens collected from 21 newborns and three patients with genetically confirmed SMA were analyzed. The SMA controls included two patients with homozygous SMN1 deletion and one with compound heterozygous SMN1 variants. SMN1 exon 7 copy numbers were quantified and interpreted. All newborn participants had SMN1 copy numbers above the screening cutoff value of 668 copies/µL and were classified as screening-negative. The two SMA controls with homozygous SMN1 deletion showed no detectable SMN1 amplification, which is consistent with positive screening results. In contrast, the compound heterozygous SMA control exhibited a mean SMN1 value of 7330 copies/µL, which was more than tenfold above the screening cutoff and would therefore have been classified as screening-negative; this value also fell within the range observed in the newborn cohort. This patient had a negative NBS result at birth despite subsequently developing genetically confirmed SMA. The SMA-NBS assay accurately detected patients with homozygous SMN1 deletion. However, it did not identify patients with compound heterozygous SMN1 variants. In conclusion, deletion-based SMA-NBS has an inherent false-negative limitation, and a negative screening result does not completely exclude an SMA diagnosis.