Objective Glycosyltransfersase 8 domain containing 1 ( GLT8D1 ) gene was identified to be an amyotrophic lateral sclerosis (ALS) causative gene via pedigree co-segregation and burden analysis. However, validations based on large cohort of ALS among different ethnic population are essential. We aimed to systematically screen all exons of GLT8D1 in a large cohort of Chinese ALS patients, study the genotype-phenotype correlation and explore the role of rare variants of GLT8D1 in ALS.
Methods A total of 977 sporadic ALS (sALS) and 47 familial ALS (fALS) cases underwent whole exome sequencing. Rare variants with MAF<0.1% in GLT8D1 were analyzed. Moreover, by using the controls from gnomAD database, rare variants were included in the burden analysis via 5 different algorithms.
Results We identified 1 likely pathogenic variant in the exon 4 of GLT8D1 in a fALS case and validated within the pedigree. Moreover, 3 variant of uncertain significance (VUS) in 4 patients among the 977 sALS cases 1 VUS in 1 case among the 47 fALS cases were also identified. Furthermore, in the burden analysis, there were no significant enrichment of rare variants of GLT8D1 in the whole gene level or exon 4 exclusively among Chinese patients with sALS.
Conclusion Cosegregation findings in our study further supported the pathogenic role of GLT8D1 in fALS. However, no pathogenic mutation was identified in the sALS patients, and rare variants were not enriched in the whole gene level or exon 4 of GLT8D1 among sALS patients, both of which suggested that the GLT8D1 may not play a role in Chinese patients with sALS.