Oligogenic variants in NEK1 and ATXN2 in amyotrophic lateral sclerosis: report of two cases and review of the literature.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects the upper and lower motor neurons and leads to progressive paralysis. More than 40 genes have been implicated in familial ALS, which represents about 10% of ALS cases. Some genes, including C9orf72, SOD1, FUS and TARDBP are undoubtedly considered causative, but many others have uncertain pathogenicity and low penetrance. Here, we described the cases of two siblings affected by ALS and carrying both an ATXN2 heterozygous 32 CAG trinucleotide repeat expansion and a novel NEK1 heterozygous c.1674_1677dup. The segregation of both variants in this large family with thirteen siblings may support a role for these variants as susceptibility alleles within an oligogenic model. Our review of the literature suggests that NEK1 variants are frequently found in combination with other variants and repeats expansion in the ATXN2 gene appears to be more associated with monogenic ALS, but also frequently combined with C9orf72 repeat expansion.