Contrasting clinical trajectories in two ALS patients with rare FUS variants: implications for variant interpretation, penetrance, and trial readiness

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor system. A minority of cases are associated with a genetic variant. Variants in C9orf72 , SOD1 , TARDBP , and FUS are the most common. Compared with other forms of ALS, ALS presenting with FUS variants is relatively aggressive. However, phenotypic heterogeneity has been reported. We describe two cases of ALS with rare FUS variants with contrasting clinical courses. These cases highlight the importance of the different factors that influence ALS phenotypic presentation and the challenges of variant interpretation in ALS, as outlined in the ACMG Guidelines. It is essential to recognise specific genotype-phenotype relationships and environmental factors that could alter the clinical course of the disease and affect therapeutic agent selection.