Here, whole-exome sequencing (WES) in a pilot cohort of 23 ALS patients to detect rare ALS-associated variants yielded recurrent mutations in an HSP-associated gene, SPG7. We then aimed at systematically studying the frequency, predicted consequences on the protein level, and clinical impact of SPG7 mutations in a larger European ALS cohort. This evidence concerns the gene SPG7 and amyotrophic lateral sclerosis.