Abstract
The influence of genetic factors on the prognosis of amyotrophic lateral sclerosis (ALS) has attracted considerable attention, with numerous studies exploring this relationship in clinically diagnosed patients. The present study attempted to clarify the precise impact of genetic factors on prognosis in patients with pathologically confirmed sporadic ALS. We conducted exome analysis on 137 consecutively autopsied patients with sporadic ALS exhibiting TDP-43 pathology, screening for non-synonymous or splice-site rare variants (RVs) in ALS-related genes. The impact of these variants on ALS prognosis was subsequently assessed. The exome analysis identified 31 RVs in 27 of the 137 patients, including TAF15 exon 15 insertion/deletion mutations (TAF15-15 indels) in 9 patients. Patients harboring RVs had significantly shorter survival times (median 18.0 months) than those without RVs (28.5 months), as determined by log-rank test (p = 0.02). Notably, the 9 cases with TAF15-15 indels demonstrated a significantly poorer outcome (15.0 months, p = 3e-06). Lattice Simulation of Sticker-Spacer Interactions (LASSI) simulations revealed stronger negative sticker-sticker interactions, and a tendency toward lower saturation concentration and higher dense-phase concentration in TAF15-15 indel proteins, suggesting enhanced condensation. The present analysis of pathologically diagnosed ALS patients has yielded genetic factors that could potentially aid more accurate diagnosis and prognostication. The frequent identification of TAF15-15 indels among ALS cases, and their association with significantly poorer outcome, suggests that this type of mutation could be prognostically significant in ALS. Furthermore, the mechanism by which TAF15-15 indels influence the course of ALS could be a promising target for future treatments.