The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

中文翻译：

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携带两个拷贝的 C9orf72 六核苷酸重复中等长度等位基因是芬兰人群中 ALS 的危险因素

C9orf72 基因内含子 1 中的六核苷酸重复扩增导致肌萎缩侧索硬化 (ALS) 和额颞叶痴呆。除了致病性扩增的影响外，还提出了中等长度等位基因在 ALS、皮质基底节变性和帕金森病中的作用。由于具有超过 20 个重复的中等长度等位基因的稀有性及其频率的地理变异性，需要考虑人口分层的大型研究来阐明它们的影响。为此，我们使用重复引发 PCR 和验证性 PCR 测定来确定来自芬兰的 705 名 ALS 患者和 3958 名对照的 C9orf72 重复等位基因长度。在排除扩增载体（25.5% 的 ALS 患者和 0.2% 的对照）后，我们使用几个中等长度等位基因阈值（7-45、17-45、21-45、24-45 和 24-30）比较了 525 例 ALS 病例和 3950 例对照的中等长度等位基因携带者的频率。当我们将对照组分为三个年龄组（18-65 岁， 66-84 岁和 85-105 岁）。两个中等长度等位基因的携带与 ALS 相关，当较长的等位基因≥ 17 次重复（p = 0.002，OR 5.32 95% CI 2.02–14.05）或≥ 21 次重复（p = 0.00016，OR 15.21 95% CI 3.79– 61.0)。我们的研究结果表明，当两个等位基因都存在时，中等长度等位基因是 ALS 的危险因素，而仅携带一个中等长度等位基因与 ALS 或生存无关。