Integrating LNA-qPCR and full-length SMN1 sequencing for precision SMA carrier screening: large-scale validation in 30,849 individuals.

Biallelic loss of function of SMN1, most often through homozygous deletion of exon 7, assessed by copy number quantification of that exon.

This prospective study screened carrier status for spinal muscular atrophy in 30,733 pre-pregnancy and early-pregnancy individuals without a family history, across 14 cities of Hunan Province, China, between September 2020 and September 2025. SMN1 exon 7 copy number was measured by locked nucleic acid quantitative PCR (LNA-qPCR) with MLPA validation on 2,000 randomly selected samples; 438 carriers were identified, a frequency of 1/69 (1.43%), ranging from 0.80% to 1.98% across regions. LNA-qPCR achieved 100% sensitivity and 99.85% specificity, and scrutiny of rare false positives uncovered two previously unreported SNPs, c.835-44G>A and c.835-50A>G in SMN1, which interfere with primer binding and may be common diagnostic confounders in the Chinese population. Full-length SMN1 amplification with Sanger sequencing, applied to suspected children and fetuses from 58 high-risk couples, established the genetic aetiology for seven previously undiagnosed patients. Prenatal diagnosis in 50 at-risk pregnancies identified 16 affected fetuses.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A carrier frequency of 1/69 and 99.85% specificity strengthen the case for organised preconception screening, but these figures come from a single Chinese province and do not transfer unchanged elsewhere. The most directly useful laboratory finding is the pair of SNPs interfering with primer binding: it is a reminder that a borderline or discordant copy number result warrants an orthogonal method before a non-carrier status is reported. The 16 affected fetuses came from pregnancies already flagged as high risk, so this yield does not measure the benefit of population screening, and the study says nothing about the counselling delivered downstream.

Analysis by Dr Thibaut Benquey