Burden of pathogenetic and likely pathogenetic variants in SPG7, SPG11 and AP4 genes in Amyotrophic Lateral Sclerosis. A case-control study

Background: There is evidence that some Hereditary Spastic Paraplegia (HSP) genes are linked to Amyotrophic Lateral Sclerosis (ALS). In particular, KIF5A and SPG11 genes, which cause two different forms of HSP, are also associated with adult-onset and Juvenile ALS, respectively. Objectives: To study the frequencies of pathogenetic and likely pathogenetic variants in HSP genes in ALS patients and to determine whether they act as predisposing factors. Methods: We analysed 72 HSP-associated genes in 1024 ALS and 44 Primary Lateral Sclerosis patients and applied customized ACMG criteria to identify pathogenic and likely pathogenic variants. Based on the frequency of identified variants, six genes, including SPG7, SPG11 and the four genes encoding the subunits of the AP4 adaptor protein, were selected for analysis in an additional cohort of 481 ALS patients. Overall results on 1549 patients were compared with 1138 controls. Results: The frequency of variants in SPG7 gene was 0.45% (7/1549) in patients vs 0.18% (2/1138) in controls (p = 0.19), in SPG11 was 0.77% (12/1549) in cases and 0.26% (3/1138) in controls (p = 0.06), in AP4 genes was 0.64% (10/1549) in patients and 0.26% (3/1138) in controls (p = 0.13). The total number of variants detected across SPG7, SPG11 and AP4 genes was statistically different between patients and controls (1.87% vs 0.7%; p = 0.006). Conclusions: We found a significant enrichment of variants in a set of HSP genes, including SPG7, SPG11 and AP4 genes, in a large cohort of ALS patients, suggesting that they may act as predisposing factors for ALS