Rare SMA Patients: A Comprehensive Look at Clinical Features, Genetic Profiles and Therapeutic Approaches

Spinal muscular atrophy 5q (5q SMA) is one of the most prevalent autosomal recessive disorders globally. The underlying cause of 5q SMA is attributed to variants in SMN1. To date, there are no reported cases of gene-based therapy in rare patients with 5q SMA caused by subtle SMN1 variants of unknown clinical significance. We included 10 patients with the clinical manifestations of 5q SMA associated with intragenic variants in combination with a heterozygous SMN1 deletion in this retrospective study. Previously reported pathogenic or likely pathogenic variants were identified (e.g., c.*3+1del, c.815A>G (p.Tyr272Cys), and c.821C>T (p.Thr274Ile)). Variants of unknown clinical significance were also found, including a recurrent, previously unreported variant c.80A>C (p.Gln27Pro). We also report detailed molecular genetic and clinical data on 9 patients with 5q SMA. In addition, we provide results from the cohort of patients with gene-based therapy, consistent with data from patients with a homozygous SMN1 deletion.