Objective: To identify novel disease-causing genes for amyotrophic lateral sclerosis (ALS). Design, Setting, and Patients: We carried out a systematic mutation screening of the entire coding regions of 29 candidate genes encoding critically important proteins for proper differentiation and development of corticospinal motor neurons in 190 patients with familial and sporadic ALS. Main Outcome Measures: We focused our analysis on coding variants and evaluated the distribution of nonsynonymous and synonymous variants in our cohort of patients with ALS. Results: We identified 40 novel nonsynonymous variants and showed a significant excess of unique nonsynonymous variants in our cohort of patients with ALS, which suggests the presence of ALS-predisposing mutations. Conclusions: Using a multifaceted approach based on the functional prediction of missense variants, the conservation of the altered amino acid, and the cosegregation of the variants identified in familial cases, we identified several promising novel genes for ALS such as LUM and CRYM. We have also highlighted the analytical challenges of large-scale sequencing screens to detect disease-causing variants.
ASJC Scopus subject areas
- Arts and Humanities (miscellaneous)
- Clinical Neurology