Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort

Abstract

ObjectiveTo assess the burden of rare genetic variants and to estimate the contribution of known ALS genes in an Italian population-based cohort we performed whole genome sequencing in 959 ALS patients and 677 matched healthy controls.MethodsWe performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS, PARALS). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population.ResultsA total of 959 ALS patients were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with SOD1, whose rare variants are the second most common cause of disease after C9orf72 expansion. A lower signal was observed for TARDBP, proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited.ConclusionsWe identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic utility.

GBA variants influence cognitive status in amyotrophic lateral sclerosis

“…We examined the GBA variants' association with the risk of cognitive impairment in 751 patients with ALS from the population-based Piemonte and Valle d'Aosta Register for ALS that had undergone both a detailed neuropsychological evaluation and a whole-genome sequencing screening. 3 Patients were classified as ALS with normal cognitive function (ALS-CN), ALS-FTD and ALS with intermediate cognitive deficits. The characteristics of the study population and a detailed description of neuropsychological testing and genetic screening are reported in online supplementarl materials in the Methods section.…”

“…To assess whether pathogenic rare variants (minor allele frequency<1%) in GBA contribute to cognitive decline risk in ALS, a genebased rare variants association test was performed as previously described. 3 In the following step of the analysis, only variants known to be a risk factor for cognitive decline in PD were considered. First, a binomial test was used to assess the prevalence of GBA mutations across cognitive groups.…”

“…We examined the GBA variants’ association with the risk of cognitive impairment in 751 patients with ALS from the population-based Piemonte and Valle d’Aosta Register for ALS that had undergone both a detailed neuropsychological evaluation and a whole-genome sequencing screening 3. Patients were classified as ALS with normal cognitive function (ALS-CN), ALS-FTD and ALS with intermediate cognitive deficits.…”

“…A mutational screening of GBA exonic variants was performed and their frequencies were compared with an internal control cohort (see online supplemental methods, Subjects). To assess whether pathogenic rare variants (minor allele frequency<1%) in GBA contribute to cognitive decline risk in ALS, a gene-based rare variants association test was performed as previously described 3. In the following step of the analysis, only variants known to be a risk factor for cognitive decline in PD were considered.…”

Genetic testing for amyotrophic lateral sclerosis in Canada – an assessment of current practices

“…There is an emerging appreciation for more widespread access to genetic testing in facilitating access to genetically-targeted therapies (9,10).…”