Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Neurobiol Aging. 2021 May;101:298.e17-298.e21. doi: 10.1016/j.neurobiolaging.2020.10.017. Epub 2020 Oct 22.
The glycosyltransferase 8 domain containing 1 (GLT8D1) gene was identified to be an amyotrophic lateral sclerosis (ALS)-causative gene via pedigree cosegregation and burden analysis. In the present study, 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases underwent whole-exome sequencing. Rare variants with minor allele frequency <0.1% in GLT8D1 were analyzed. One likely pathogenic variant in the exon 4 was identified in a fALS case and validated within the family. Moreover, 3 rare variants of uncertain significance in 4 patients with sALS and 1 rare variant of uncertain significance in 1 patient with fALS were also identified. Furthermore, by using the East Asian controls from the gnomAD database, there was no significant enrichment of rare variants of GLT8D1 at the whole-gene level or the exon 4-specific level in Chinese patients with sALS. In conclusion, cosegregation findings further support the pathogenic role of GLT8D1 in fALS. However, no pathogenic mutation and no enrichment of rare variants were found in patients with sALS, which implies that GLT8D1 may not play a role in Chinese patients with sALS.
通过家系共分离和负担分析，发现糖基转移酶 8 结构域包含 1 号（GLT8D1）基因是肌萎缩侧索硬化症（ALS）的致病基因。本研究对 977 例中国散发性 ALS（sALS）病例和 47 例中国家族性 ALS（fALS）病例进行了全外显子组测序。分析了 GLT8D1 中次要等位基因频率<0.1%的罕见变异。在一个 fALS 病例中发现了外显子 4 中的一个可能致病变异，并在家族内进行了验证。此外，在 4 例 sALS 患者中发现了 3 个意义未明的罕见变异，在 1 例 fALS 患者中发现了 1 个意义未明的罕见变异。此外，通过使用 gnomAD 数据库中的东亚对照，在 sALS 中国患者中，GLT8D1 的全基因水平或外显子 4 特异性水平均未发现罕见变异的显著富集。总之，共分离发现进一步支持 GLT8D1 在 fALS 中的致病作用。然而，在 sALS 患者中未发现致病性突变和罕见变异的富集，这表明 GLT8D1 可能在 sALS 中国患者中不起作用。
