HealthDay News — Rare variants in known amyotrophic lateral sclerosis genes have been found in a significant proportion of patients with familial and sporadic disease. The variants are potentially pathogenic and seem to influence disease onset, according to a study published in the Annals of Neurology.

Janet Cady, from Washington University in St. Louis, and colleagues used targeted pooled-sample sequencing to identify variants in 17 amyotrophic lateral sclerosis (ALS) genes from 391 ALS patients in the United States. ATXN2 and C9ORF72 expansion sizes were defined using fragment size analysis.

Genotype-phenotype associations were made with individual variant and with total variant burden. At both single variant and gene level, the authors examined rare variant associations for the risk of ALS.

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The researchers found that 64.3% and 27.8% of familial and sporadic subjects, respectively, carried potentially pathogenic novel or rare coding variants that were identified by sequencing or an expanded repeat in ATXN2 and C9ORF72.

Overall, variants in more than one ALS gene were seen in 3.8% of subjects, and in these individuals, disease onset occurred more than 10 years earlier (P=0.0046) compared with those with a variant in a single gene. There was no correlation between the number of potentially pathogenic coding variants and disease duration or site of onset.

“A significant number of subjects carried variants in more than one gene, which influenced the age of symptom onset and supports oligogenic inheritance as relevant to disease pathogenesis,” the researchers wrote.


  1. Cady J, Allred P, Bali T, et al. ALS onset is influenced by the burden of rare variants in known ALS genes. Ann Neurol. 2014; doi:10.1002/ana.24306.

Disclosures: Several authors disclosed financial ties to the pharmaceutical industry.