第七届北京罕见病学术大会暨2019京津冀罕见病学术大会征文（43）

Department of Neurology， Peking University Third Hospital， Beijing， China

Correspondence to Professor Dongsheng Fan， Department of Neurology， Peking University Third Hospital

Xiaolu Liu1， Ji He1， Jiao Li， Lu Chen， Nan Zhang， Lu Tang， Xiangyi Liu， Yan Ma and Dongsheng Fan

1 Xiaolu Liu and Ji He contributed equally.

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear etiology. Recently， TANK-binding kinase 1 (TBK1) gene has been reported as a risk gene of ALS/FTD. In this study， we performed a screening of TBK1 variants to determine the frequency of them in a large cohort of Chinese familial and sporadic ALS patients.

Method: In this study， we performed a screening of TBK1 variants in 69 FALS patients and 611 SALS patients from mainland of China. All 20 coding exons and the exon-intron flanking regions (within 2 nucleotides of exon boundary) of TBK1 were amplified and sequenced using the method of Sanger sequencing. For the patients with variants in TBK1， we sequenced other common pathogenic genes (SOD1， FUS， TARDBP and C9orf72) and ALS genes also involved in autophagy pathway (OPTN and SQSTM1).

Results: Totally， we identified 10 non-synonymous variations in 11 unrelated ALS patients. 9 of them were missense variations， the other one p.L508CfsX26 was a splice site variation. The patient with p.K291R had a family history of ALS. Other variants were detected in SALS patients. All the variants were absent in more than 287 controls and predicted Disease causing by MutationTaster. For the variants detected in ALS patients， 5 located in Kinase domain， 4 in Coiled coil 1 domain and 1 in Ubiquitin-like domain. Interestingly， 3 patients with variants in TBK1 carried another variants in other genes related with autophagy: p.G175S in TBK1 and p.P392L in SQSTM1(rs104893941); p.D534H in TBK1 and p.E372D in SQSTM1; p.P544L in TBK1(rs753372288) and p.H476N in OPTN.

Conclusion: We have found that TBK1 variants account for about 1.6% of Chinese ALS patients. It’s necessary to make the screening of this gene in ALS patients， especially in the group with variants in other genes related with the pathway of autophagy.

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