Submission Details

LGALSL codes for the galectin-like protein, previously known as lectin, galactoside-binding-like. While the function of this protein is largely unknown, other members of the galectin family (LGALS1 and LGALS3) have been implicated in ALS disease processes and progression. LGALSL was identified as a candidate gene responsible for ALS by a single burden collapsing analysis in a large cohort (PMID: 30940688). This cohort of 3,239 ALS cases and 11,808 controls of matched and diverse genetic ancestry were subjected to a novel gene-collapsing analysis whose unit of collapsing was regional intolerance to missense variation rather than the gene itself. This novel approach identified LGALS as the third enriched gene, following known ALS genes: SOD1 and TARDBP. Enrichment of this gene originates from one specific domain (a region comprising 378 bp that is mapped to a conserved protein domain intolerant to variation) (OR = 14.63; P = 2.29 × 10−6). LGALSL loss of function variants were only identified in cases and absent from the nearly 12,000 controls, and further were only identified in 3 out of 60,033 individuals in ExAC. Effects of population and gender as possible covariates were analyzed using the Firth logistic regression and revealed a reduction in genomic inflation factor from λ = 1.14 to λ = 1.04, and a strengthened P-value of 5.84 × 10−7. LGALSL enrichment was replicated in a data set of 830 cases and 1858 controls that were available at Columbia University and were subjected to the same intolerance-informed analysis as the original cohort (OR 4.5, not statistically significant but demonstrates same direction of enrichment). Using the Cochran-Mantel-Haenszel (CMH) test to combine the original and replication cohorts, a final, combined P = 1.54 × 10−7 and a common odds-ratio of 11.35 for LGALSL was determined. This case-control study was allotted 6 genetic-evidence points due to it involving a large number of cases and controls studied that were appropriately matched by genetic ancestry, lack of bias or confounding variables, findings replicated in a second cohort, and an odds ratio that was highly statistically significant. While this study on its own provides evidence to support a limited gene-disease relationship between LGALSL and ALS, this study has not yet been replicated, and no mutations segregating in familial ALS or ALS-FTD have been reported. Additionally, no experimental evidence has been reported on this gene. Until additional genetic and experimental evidence are reported on this gene, it remains classified as a limited-evidence gene.