Objective: To explore the association between rare HSPB1 variants and amyotrophic lateral sclerosis (ALS).
Methods: We performed next-generation sequencing for 166 Chinese ALS patients to screen for possible pathogenic rare variants of HSPB1. The control individuals were obtained from 1000 Genome Project and an in-house whole-exome sequencing database. The Sequence Kernel Association Test (SKAT) and the SKAT-optimal test (SKAT-O) were used to identify the association between rare HSPB1 variants and ALS.
Results: We identified 3 possible pathogenic rare variants of HSPB1 (all were missenses), including c.379C>T (p.R127W), c.446A>C (p.D149A) and c.451A>C (p.T151P). Compared with 1000 Genome Project, SKAT p=3.61×10-7 and SKAT-O p=1.62×10-6; while compared with the in-house database, SKAT p=9.99×10-4, SKAT-O p= 1.80×10-3. We analyzed the phenotypes of rare HSPB1 variant carriers and found no specific clinical characteristics associated with these variants.
Conclusions: Rare variants of HSPB1 are probably associated with the pathogenesis of ALS.
目的: 探讨HSPB1基因罕见变异与肌萎缩侧索硬化（ALS）发病的相关性。
方法: 对166例中国ALS患者进行二代测序基因检测，筛选出HSPB1基因可能的致病性罕见变异，分别与千人计划及国内全外显子测序健康对照数据库比对分析，进行序列核关联性检验（SKAT）及优化的SKAT（SKAT-O）。
结果: 本研究共筛选出3个HSPB1基因可能的致病性罕见变异：c.379C>T（p. R127W）、c.446A>C（p.D149A）及c.451A>C（p.T151P），均为错义突变。以千人计划作为对照，SKAT p=3.61×10-7，SKAT-O p= 1.62×10-6；以国内全外显子测序健康对照数据库作为对照，SKAT p=9.99×10-4，SKAT-O p=1.80×10-3。未发现该基因罕见变异携带者的特征性临床表型特点。
结论: HSPB1基因罕见变异可能与ALS发病存在相关性。
Keywords: HSPB1 gene; Sequence Kernel Association Test; amyotrophic lateral sclerosis; rare variants.