KIF5A p.Pro986Leu Risk Variant and Accelerated Progression of Amyotrophic Lateral Sclerosis

This study explored the impact of KIF5A rs113247976 (p.Pro986Leu), a risk allele for amyotrophic lateral sclerosis (ALS), on phenotypic variability in two Italian ALS cohorts (discovery, n = 865; replication, n = 1174). The minor allele (T) frequency was 0.015. No patients were homozygous (TT), allowing comparison between wild type and heterozygous carriers only. Heterozygous carriers showed faster disease progression (ALSFRS-R preslope). Findings were validated across both cohorts. Multiple linear regression identified p.Leu986 and age at onset as ALSFRS-R preslope predictors. In conclusion, heterozygous p.Leu986 in KIF5A is associated with faster ALS progression, supporting its consideration for genetic screening in clinical trials.