Genetic Variants Associated With Neurodegenerative Disorders in Patients With Amyotrophic Lateral Sclerosis and Phenotypic Variability

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BACKGROUND AND OBJECTIVES: The genetic contribution to clinical heterogeneity in amyotrophic lateral sclerosis (ALS) remains poorly understood, particularly regarding the role of genes associated with other neurodegenerative disorders. This study aimed to determine whether rare variants in neurodegeneration-associated genes influence ALS risk and clinical phenotype. METHODS: This case-control study included patients with ALS without pathogenic variants in major ALS genes from the population-based Piemonte and Valle d'Aosta Register for ALS and matched controls. High-impact rare variants (minor allele frequency <0.01% or novel) in 151 genes associated with neurodegenerative disorders were identified through whole-genome sequencing. Main outcomes included ALS risk, motor phenotype, cognitive status, and survival. Findings were replicated in the Project MinE dataset (6,596 ALS cases, 2,454 controls). RESULTS: = 0.003). DISCUSSION: Rare variants in genes associated with other neurodegenerative disorders influence both ALS susceptibility and clinical features, highlighting genetic pleiotropy across neurodegenerative diseases. Our findings support a model in which ALS arises from a complex and heterogeneous genetic landscape involving multiple variants, often shared with other neurodegenerative conditions, that shape disease expression. Although these findings suggest potential future expansion of genetic screening beyond classical ALS genes, such variants should be interpreted cautiously in clinical practice pending further functional validation.

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