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

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 – The study population consisted of 791 ALS patients (median age 67.9 years; 46.3% women) and 747 matched controls. One hundred twenty-seven ALS cases (16.1%) carried at least one rare variant in neurodegeneration-associated genes compared with 91 (12.2%) controls (odds ratio [OR] 1.37; 95% CI 1.04–1.80; p = 0.027). In particular, novel variants in Parkinson disease–associated genes (OR 3.62; 95% CI 1.33–9.80; p = 0.01) and hereditary neuropathy genes (OR 3.30; 95% CI 1.55–7.03; p = 0.002) conferred a 3-fold increased risk. These findings were independently replicated in the Project MinE dataset (OR 1.43; 95% CI 1.30–1.57; p < 0.001). Stratified analysis also confirmed the enrichment of rare variants in Parkinson disease and hereditary neuropathy-associated genes. Variant carriers were more likely to present with the flail arm phenotype (OR 2.05; 95% CI 1.05–3.98; p = 0.03) and showed increased risk of frontotemporal dementia (OR 1.85; 95% CI 1.04–3.21; p = 0.03) and shorter survival (hazard ratio 1.99; 95% CI 1.26–3.14; p = 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.