Xi Zhengrui, Zinman Lorne, Grinberg Yakov, Moreno Danielle, Sato Christine, Bilbao Juan M, Ghani Mahdi, Hernández Isabel, Ruiz Agustín, Boada Mercè, Morón Francisco J, Lang Anthony E, Marras Connie, Bruni Amalia, Colao Rosanna, Maletta Raffaele G, Puccio Gianfranco, Rainero Innocenzo, Pinessi Lorenzo, Galimberti Daniela, Morrison Karen E, Moorby Catriona, Stockton Joanne D, Masellis Mario, Black Sandra E, Hazrati Lili-Naz, Liang Yan, van Haersma de With Jan, Fornazzari Luis, Villagra Roque, Rojas-Garcia Ricardo, Clarimón Jordi, Mayeux Richard, Robertson Janice, St George-Hyslop Peter, Rogaeva Ekaterina
Arch Neurol. 2012 Dec;69(12):1583-90. doi: 10.1001/archneurol.2012.2016.
OBJECTIVE To estimate the allele frequency of C9orf72 (G4C2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD). DESIGN The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes. SETTING Hospitals specializing in neurodegenerative disorders. SUBJECTS We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation. MAIN OUTCOME MEASURE The expansion frequency. RESULTS Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20-29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43-positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus. CONCLUSIONS The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.
目的 评估肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTLD）、阿尔茨海默病（AD）和帕金森病（PD）中C9orf72（G4C2）重复序列的等位基因频率。设计 通过两步基因分型策略估计重复序列的数量。对于扩增携带者，我们对重复序列侧翼区域进行测序，并获得APOE基因型和MAPT H1/H2单倍型。单位 专门治疗神经退行性疾病的医院。对象 我们分析了520例FTLD患者、389例ALS患者、424例AD患者、289例PD患者、602例对照、18个家系以及29例携带LRRK2 G2019S突变的PD患者。主要观察指标 扩增频率。结果 根据先前设定的阈值（>30次重复），在9.3%的ALS患者、5.2%的FTLD患者和0.7%的PD患者中检测到扩增，但在对照或AD患者中未检测到。它与ALS或FTLD家族史以及FTLD发病年龄显著相关。表型变异（ALS与FTLD）与MAPT、APOE或重复序列侧翼区域变异无关。两名PD患者为分别携带39次和32次重复序列的携带者，其病理意义存疑，因为39次重复等位基因与PD不连锁。在G2019S携带者和TAR DNA结合蛋白43阳性包涵体的AD病例中未发现扩增或中间等位基因（20 - 29次重复）。令人惊讶的是，与对照相比，所有4种神经退行性疾病中10次重复等位基因的频率均略有增加，表明C9orf72基因座存在未知的风险变异。结论 C9orf72扩增是ALS和FTLD的常见病因，但不是AD或PD的病因。我们的研究引发了对病理重复数可靠阈值的关注，这在基因筛查应用中很重要。
