Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.
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DOI：
10.1016/s1474-4422(12)70043-1
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发表时间：
2012-04
期刊：
影响因子：
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通讯作者：
Traynor BJ
中科院分区：
文献类型：
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作者：
Majounie E;Renton AE;Mok K;Dopper EG;Waite A;Rollinson S;Chiò A;Restagno G;Nicolaou N;Simon-Sanchez J;van Swieten JC;Abramzon Y;Johnson JO;Sendtner M;Pamphlett R;Orrell RW;Mead S;Sidle KC;Houlden H;Rohrer JD;Morrison KE;Pall H;Talbot K;Ansorge O;Chromosome 9-ALS/FTD Consortium;French research network on FTLD/FTLD/ALS;ITALSGEN Consortium;Hernandez DG;Arepalli S;Sabatelli M;Mora G;Corbo M;Giannini F;Calvo A;Englund E;Borghero G;Floris GL;Remes AM;Laaksovirta H;McCluskey L;Trojanowski JQ;Van Deerlin VM;Schellenberg GD;Nalls MA;Drory VE;Lu CS;Yeh TH;Ishiura H;Takahashi Y;Tsuji S;Le Ber I;Brice A;Drepper C;Williams N;Kirby J;Shaw P;Hardy J;Tienari PJ;Heutink P;Morris HR;Pickering-Brown S;Traynor BJ
我们的目的是准确估计C9 orf 72中六核苷酸重复扩增的频率，该频率与大部分肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）病例相关。我们使用重复引物PCR检测法筛选了来自全球17个地区的4448例ALS（埃尔埃斯科里亚标准）和1425例FTD（Lund-Manchester标准）患者的GGGGCC六核苷酸扩增。我们根据在样本采集时自我报告的类似神经退行性疾病家族史评估家族性疾病状态。我们比较了262例携带扩展的患者的单倍型数据与已知的芬兰创始人风险单倍型的染色体位点。我们使用Kaplan-Meier方法计算了603例扩展个体的年龄相关性。在散发性ALS患者中，我们在来自美国、欧洲和澳大利亚的3377名白色个体中的236名（7.0%）、来自美国的49名黑人个体中的2名（4.1%）和来自美国的72名西班牙裔个体中的6名（8.3%）中确定了重复扩增。该突变存在于来自欧洲和美国的552名患有家族性ALS的白色个体中的217名（39.3%）中。981例散发性FTD欧洲白色患者中有59例（6.0%）发生突变，400例家族性FTD欧洲白色患者中有99例（24.8%）发生突变。其他种族的数据很少，但我们确定了一个亚洲患者的家族性ALS（从20评估）和两个家族性FTD（从三个评估）谁携带突变。3名美国原住民或360名来自亚洲或太平洋岛屿的散发性ALS患者或41名散发性FTD亚洲患者均未携带该突变。所有重复扩增的患者都有（部分或全部）创始人单倍型，这表明大约在1500年前发生了一次性扩增。致病性扩张在35岁以下的个体中是非渗透性的，到58岁时渗透率为50%，到80岁时几乎完全渗透。C9 orf 72中常见的孟德尔遗传病变与许多散发性和家族性ALS和FTD病例有关。在对患有这些致命神经退行性疾病的患者进行管理和遗传咨询时，应考虑对这种致病性扩展进行检测。完整的资金来源列在文件的末尾（见鸣谢）。
We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Full funding sources listed at end of paper (see Acknowledgments).