Variants in a Cohort of Italian Patients With Amyotrophic Lateral Sclerosis.

INTRODUCTION

In the last few years, different studies highlighted a significant enrichment of loss of function (LoF) variants in amyotrophic lateral sclerosis (ALS), and an additional role for the p.Arg261His missense variant in the disease susceptibility. Several other missense variants have been described so far, whose pathogenic relevance remains however unclear since many of them have been reported in both patients and controls. This study aimed to investigate the presence of variants and their correlation with phenotype in a cohort of Italian patients with ALS.

METHODS

We sequenced a cohort of 350 unrelated Italian patients with ALS by next-generation sequencing (NGS) and then we analyzed the clinical features of carriers.

RESULTS

We detected 20 different rare variants (four LoF and 16 missense) in 33 unrelated patients with sporadic ALS (sALS). The four LoF variants (two frameshift and two splice-site variants) were all novel. The p.Arg261His missense variant was enriched in the patients' cohort ( < 0.001). Excluding this variant from counting, the difference in the frequency of rare missense variants between patients and controls was not statistically significant. carriers had a higher frequency of flail arm (FA) phenotype compared with the other patients of the cohort (29.2% vs. 6.4%). Nine carriers (37.5%) also harbored variants in other ALS-related genes.

CONCLUSION

This study confirms that LoF and p.Arg261. His missense variants are associated with ALS in an Italian ALS cohort and suggests a correlation between the presence of variants and FA phenotype.