ATAXIN2 CAG-repeat length in Italians patients with amyotrophic lateral sclerosis : risk factor or variant phenotype? Implication for genetic testing and counseling

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving cortical and spinal motor neurons. Several studies indicated that intermediate CAG expansions in ataxin-2 gene (. ATXN2) are associated with increased risk of ALS. We analyzed . ATXN2 CAG repeats in 658 sporadic ALS patients (SALS), 143 familial ALS cases (FALS), 231 sporadic ataxic subjects, and 551 control subjects. The frequency of . ATXN2 alleles with 27-30 repeats was similar in SALS and control subjects. Fifteen SALS subjects carried ≥ 31 CAG repeats. This difference was statistically significant (. p = 0.0014). No alleles with ≥ 34 CAG were found. In FALS, the distribution of . ATXN2 alleles was similar to control subjects. Our results further contributed in refining CAG-repeat range significantly associated with sporadic ALS. Literature data and our findings indicate that only alleles with ≥ 31 CAG may represent low-penetrance disease/susceptibility alleles associated with variable neurodegenerative phenotypes, including cerebellar ataxia, parkinsonism, and ALS. Overlapping phenotypes should be considered in genetic testing and counseling, both for patients and at-risk family members.