Clinical and genetic characterization of FUS-associated ALS in a tertiary cohort.

An understanding of FUS-related ALS is becoming increasingly actionable with the emergence of targeted therapies. We retrospectively reviewed patients with amyotrophic lateral sclerosis and reported FUS variants evaluated across all Mayo Clinic sites between January 2009 and June 2026. Variants were reevaluated according to ACMG/AMP criteria, and clinical and genetic data were abstracted from medical records. The primary cohort included 12 unrelated patients with pathogenic or likely pathogenic (P/LP) FUS variants; 6 patients with variants of uncertain significance were retained descriptively. Pathogenic variants clustered in the C-terminal region, including one previously unreported likely pathogenic frameshift variant, c.1491_1494dup. Patients with pathogenic variants showed early-onset, rapidly progressive disease with frequent bulbar or respiratory onset, predominant lower motor neuron findings, and short survival. Observed phenotypes were broadly consistent with previous variant-specific reports. These findings expand variant-specific natural history data in FUS-ALS and may inform prognosis, patient stratification, and the interpretation of emerging FUS-targeted therapeutic studies.