Clinically discordant siblings with spinal muscular atrophy: insights from their patient-specific iPSC-derived motor neurons and literature review.

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by homozygous loss of the SMN1 gene. Copy number of the nearly identical paralog, SMN2, correlates with disease severity. SMN2 is the primary modifier of SMA, with only a few other modifiers reported. We reviewed the literature of rare siblings affected by SMA that show discordance in clinical presentation despite having the same number of SMN2 copies, which predicts the presence of genetic modifiers. We further recruited a sibling pair with discordant clinical presentations and performed detailed characterization. We utilized droplet digital PCR for deletion duplication testing and Sanger sequencing for analysis of the SMN2 exons 1-7 which confirmed zero copies of SMN1, four copies of SMN2, and no SMN2 modifying variants. Skin fibroblasts from each sibling were collected, reprogrammed into iPSCs, and differentiated to motor neurons. Patient-specific motor neurons revealed similar levels of SMN protein between the two siblings. Patient-specific iPSC-derived motor neurons collected from discordant siblings reported here may represent a powerful model for the discovery of SMN-independent modifiers.