title: Large C9orf72 repeat expansions are seen in Chinese patients with sporadic amyotrophic lateral sclerosis.
abstract: An intronic GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene was considered as the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasian populations. Using repeat-primed polymerase chain reaction analysis and Southern blotting methods, we assessed the frequency and size of hexanucleotide repeat expansion in a cohort of 918 sporadic ALS (SALS) patients and 632 control individuals of Han Chinese origin. We identified 8 (0.87%) of the SALS patients and none of control individuals as carriers of C9orf72 expansions with 700-3500 repeats. A comprehensive neuropsychological battery was conducted on 4 expansion-positive ALS patients, where 3 patients were found to have cognitive impairment. All expansion-positive patients were genotyped for the previously reported 20 single-nucleotide polymorphism (SNP) risk haplotypes on chromosome 9p21. Among them, 13 SNP risk haplotypes were shared in all expansion carriers, suggesting a common founder from European ancestry. Further meta-analysis demonstrated that the intermediate expansion size with 24-30 repeats, rare in both patients and controls, were significantly associated with the risk for ALS. To our knowledge, this is the first study to identify a proportion of Chinese SALS patients carrying this pathologic expansion of up to ∼3500 repeats and to completely elaborate the 20-SNP risk haplotypes in Chinese expansion-positive patients, providing indispensable evidence for the origin, geographical range, and population prevalence of the C9orf72-associated ALS.
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Bei
authors.initials: B
authors.lastname: Cao
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Ruwei
authors.initials: R
authors.lastname: Ou
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Bi
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China. Electronic address: hfshang2002@163.com.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Shang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D000073885:C9orf72 Protein; D003072:Cognition Disorders / Q000235:genetics; D015331:Cohort Studies; D056726:Genetic Association Studies; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011506:Proteins / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D012306:Risk
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins
keywords: Amyotrophic lateral sclerosis; C9orf72; Chinese population; Cognitive impairment; Haplotype analysis; Meta-analysis; Southern blotting