(HealthDay News) — Rare and potentially pathogenic variants in known amyotrophic lateral sclerosis (ALS) genes are present in a considerable proportion of patients with familial and sporadic disease, and the burden of variants influences disease onset, according to a study published online November 7 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 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.
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 to 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 authors write.
Several authors disclosed financial ties to the pharmaceutical industry.