Detection and characterization of SMN1 deletions in type IV spinal muscular atrophy using long-read whole-genome sequencing.

Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily caused by homozygous deletion of the SMN1 gene, with disease severity influenced by SMN2 copy number. Detecting SMN1 deletions is complicated by high sequence homology with SMN2 and complex genomic architecture. Here we applied long-read whole-genome sequencing (LR-WGS), multiplex ligation-dependent probe amplification (MLPA), and targeted PCR to two adult patients with type IV SMA. We identified and precisely mapped two novel large deletions encompassing the entire SMN1 locus and observed significantly reduced full-length SMN mRNA levels. Our findings demonstrate LR-WGS's capability to resolve complex structural variants in highly homologous regions. Integrating LR-WGS with orthogonal validation enhances diagnostic precision, informing genetic counseling and advancing molecular diagnostics for SMA.