Characterizing SMN1 hybrid and deletion alleles using large-scale SNP array-based SMA carrier screening
Noemi Vidal-Folch1, Christian Stout1, Jennifer Winters1
1Division of Laboratory Genetics and Genomics, Mayo Clinic, Rochester, MN, USA.
Background:
Most spinal muscular atrophy (SMA) carrier screening assays quantify SMN1 exon 7 copy number, providing limited information about the prevalence or structure of SMN1-SMN2 hybrid alleles generated through gene conversion. As long-read sequencing (LRS) studies begin to resolve these alleles at high resolution, typically in modest cohorts, large population-scale data remain essential for defining the broader allele-frequency context in which such structural signatures occur.
Methods:
We evaluated SMN1 exon 7 and exon 8 copy number in 18,015 individuals undergoing expanded carrier screening using a SNP-based array. Carriers were classified by deletion pattern, and representative cases underwent droplet digital PCR (ddPCR) to distinguish contiguous deletions from gene-conversion-derived hybrid alleles based on coordinated SMN1/SMN2 exon and intron copy number profiles.
Results:
Among 457 carriers (2.5%), exon 7-only deletions accounted for ~ 53%, while exon 7 + 8 deletions comprised ~ 47%. ddPCR showed that exon 7-only deletions predominantly represented SMN1-SMN2 hybrid alleles, whereas exon 7 + 8 deletions reflected contiguous loss of both exons. Isolated exon 8 deletions were rare (~ 0.05%) and likewise exhibited hybrid architecture. This distribution contrasts with earlier population studies reporting a predominance of exon 7 + 8 deletions and indicates that hybrid alleles constitute a substantial proportion of SMN1 deletion alleles in the general population.
Conclusions:
While hybrid resolution is not required for routine SMA carrier detection, the unexpectedly high prevalence of hybrid alleles highlights an important category of SMN1 structural variation that merits deeper investigation. These population-scale data provide a framework to guide and contextualize future LRS-based analyses aimed at resolving SMN1 gene-conversion tracts, allele structures, and potential modifier variants relevant to SMA pathogenesis and therapeutic response. Together, these findings support a more comprehensive understanding of SMN1 allele diversity as genomic technologies advance toward high-resolution characterization of the SMN locus.
Trial Registration:
Clinical trial number: not applicable.
