Exploring the Role of Variants in Italian ALS Patients

Variants in Cyclin F () have been associated to amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of in a large cohort of Italian ALS patients, to look for genotype-phenotype correlation of the mutations and to evaluate the -associated clinical features. We applied next-generation sequencing technologies on 971 unrelated Italian ALS patients and we filtered results to look for variants in gene. We identified 13 rare missense variants in 16 index cases (2 familial and 14 sporadic), with a cumulative mutational frequency of 1.6%. The most prevalent variant was p.Phe197Leu, found in three patients. The clinical presentation was heterogeneous, with a classic phenotype in eight patients, upper motor neuron dominant (UMN-D) phenotype in four patients, and flail arm in four patients. Clinical evaluation for cognitive impairment was performed in 13 patients using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) test, demonstrating that almost half of the patients ( = 6) had variable degrees of frontal dysfunction. In our cohort, we observed variants in 1.6% of patients (16/971), a percentage similar to that found in other series. Clinical presentation is heterogeneous, but variants are significantly associated to cognitive impairment. Our study expands the genetic variant spectrum in a large cohort of Italian ALS patients. Further studies are needed to assess genotype-phenotype associations of variants and to specify the role of each variant, which are quite common, especially in sALS patients.