摘要
目的探讨UBQLN2基因罕见变异与肌萎缩侧索硬化(ALS)发病的相关性。方法通过二代测序技术对2018年1月至2020年7月就诊于北京大学第三医院神经内科的ALS患者进行基因检测,筛选出UBQLN2基因可能的致病性罕见变异,分别与国际千人基因组计划(1000 Genome Project)2504个样本及国内全外显子测序健康对照数据库1812个样本比对分析,进行序列核关联性检验(SKAT)及优化的SKAT(SKAT-O),并分析其致病性罕见变异携带者的临床表型特点。结果共纳入166例中国ALS患者,家族性病例33例,散发性病例133例,男女比例为1.68∶1,发病年龄(43.8±12.2)岁,球部起病占12.7%,肢体起病占85.5%,5例为ALS合并额颞叶痴呆(FTD)(3.0%)。共筛选出3个UBQLN2基因可能的致病性罕见变异,c.128A>G(p.Lys43Arg)、c.142G>T(p.Val48Leu)及c.1451T>G(p.Val484Gly),均为错义突变,既往未见致病性报道。以1000 Genome Project作为对照,SKAT P=2.49×10^(-6),SKAT-O P=9.22×10^(-7);以国内全外显子测序健康对照数据库作为对照,SKAT P=1.42×10^(-3),SKAT-O P=1.10×10^(-3);携带UBQLN2基因罕见变异患者球部起病比例较其他患者高(2/3比19/163,P=0.042)。结论UBQLN2基因罕见变异与ALS发病存在相关性,该基因突变可能与球部起病相关。
Objective To explore the association between rare UBQLN2 variants and amyotrophic lateral sclerosis(ALS)in Chinese population,and the characteristic of phenotypes of their carriers.Methods A total of 166 ALS patients who visited Department of Neurology of Peking University Third Hospital between January 2018 and July 2020 were recruited.The next-generation sequencing was performed to screen possible pathogenic rare variants of UBQLN2.Meanwhile,control individuals were obtained from 1000 Genome Project(2504 samples)and an in-house whole-exome sequencing database(1812 samples),separately.The sequence kernel association test(SKAT)and the SKAT-optimal test(SKAT-O)were used to identify the association between UBQLN2 rare variants and ALS.The clinical characteristics of rare variant carriers were analyzed.Results A total of 33 familiar ALS and 133 sporadic ALS of Chinese ancestry were enrolled.Of the 166 ALS patients,12.7%had bulbar-onset,85.5%had limb-onset,and 5 cases were ALS with frontotemporal dementia(3.0%).The male-to-female ratio was 1.68∶1,with a mean age at symptom onset of(43.8±12.2)years.Three possible pathogenic rare variants of UBQLN2 were detected,including c.128A>G(p.Lys43Arg),c.142G>T(p.Val48Leu)and c.1451T>G(p.Val484Gly),and all of them were novel missense mutations.Compared with 1000 Genome Project,SKAT and SKAT-O showed a P value of 2.49×10^(-6)and 9.22×10^(-7),respectively.While compared with the in-house database,SKAT and SKAT-O revealed a P value of 1.42×10^(-3)and 1.10×10^(-3),respectively.Patients who carried rare UBQLN2 variants were with a higher rate of bulbar-onset(2/3 vs 19/163,P=0.042).Conclusion Rare variants of UBQLN2 are associated with ALS in Chinese population,and mutation of UBQLN2 may be relevant to bulbar-onset.
作者
陈君逸
刘向一
徐迎胜
樊东升
Chen Junyi;Liu Xiangyi;Xu Yingsheng;Fan Dongsheng(Department of Neurology,Peking University Third Hospital,Beijing 100191,China)
出处
《中华医学杂志》
CAS
CSCD
北大核心
2021年第12期846-850,共5页
National Medical Journal of China
基金
国家自然科学基金(81873784)。
