Characterizing SMN1 hybrid and deletion alleles using large-scale SNP array-based SMA carrier screening

Area of Science:

• Genetics
• Molecular Biology
• Population Genetics

Background:

• Current spinal muscular atrophy (SMA) carrier screening primarily measures SMN1 exon 7 copy number.
• This approach offers limited insight into the prevalence and structure of SMN1-SMN2 hybrid alleles, which arise from gene conversion.
• Advancements in long-read sequencing (LRS) are enabling high-resolution analysis of these complex alleles, but large-scale population data are needed.

Purpose of the Study:

• To evaluate the prevalence and characteristics of SMN1 structural variations, including hybrid alleles, in a large population undergoing carrier screening.
• To compare the distribution of SMN1 deletion patterns with previous studies and assess the contribution of hybrid alleles.
• To provide population-scale data that can inform future high-resolution genomic analyses of the SMN locus.

Main Methods:

• Analyzed SMN1 exon 7 and exon 8 copy number in 18,015 individuals using SNP-based arrays.
• Classified carriers based on deletion patterns.
• Utilized droplet digital PCR (ddPCR) in representative cases to differentiate contiguous deletions from gene-conversion-derived hybrid alleles by assessing coordinated SMN1/SMN2 exon and intron copy numbers.

Main Results:

• Identified 457 carriers (2.5%) with SMN1 deletions.
• Exon 7-only deletions (53%) and exon 7+8 deletions (47%) were observed.
• ddPCR confirmed that exon 7-only deletions predominantly represent SMN1-SMN2 hybrid alleles, while exon 7+8 deletions indicate contiguous loss. Isolated exon 8 deletions were rare (0.05%) and also showed hybrid architecture.
• The findings indicate a substantial proportion of SMN1 deletion alleles are hybrid, contrasting with prior studies.

Conclusions:

• The high prevalence of SMN1-SMN2 hybrid alleles, though not critical for routine SMA carrier detection, represents a significant category of SMN1 structural variation requiring further study.
• These population data establish a context for LRS-based investigations into SMN1 gene conversion, allele structures, and modifiers of SMA.
• A comprehensive understanding of SMN1 allele diversity is crucial as genomic technologies advance for high-resolution characterization of the SMN locus.