Neuroscience Research Australia, Sydney, Australia.
Neurology. 2012 Sep 4;79(10):995-1001. doi: 10.1212/WNL.0b013e3182684634. Epub 2012 Aug 8.
To determine the frequency of a hexanucleotide repeat expansion in C9ORF72, a gene of unknown function implicated in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), in Australian FTD patient cohorts and to examine the clinical and neuropathologic phenotypes associated with this expansion.
We examined a clinically ascertained FTD cohort (n = 89) and a neuropathologically ascertained cohort of frontotemporal lobar degeneration cases with TDP-43 pathology (FTLD-TDP) (n = 22) for the C9ORF72 hexanucleotide repeat expansion using a repeat primed PCR assay. All expansion-positive patients were genotyped for rs3849942, a surrogate marker for the chromosome 9p21 risk haplotype previously associated with FTD and ALS.
The C9ORF72 repeat expansion was detected in 10% of patients in the clinically diagnosed cohort, rising to 29% in those with a positive family history of early-onset dementia or ALS. The prevalence of psychotic features was significantly higher in expansion-positive cases (56% vs 14%). In the pathology cohort, 41% of TDP-43-positive cases harbored the repeat expansion, and all exhibited type B pathology. One of the 17 expansion-positive probands was homozygous for the "nonrisk" G allele of rs3849942.
The C9ORF72 repeat expansion is a relatively common cause of FTD in Australian populations, and is especially common in those with FTD-ALS, psychotic features, and a strong family history. Detection of a repeat expansion on the 9p21 putative "nonrisk" haplotype suggests that not all mutation carriers are necessarily descended from a common founder and indicates that the expansion may have occurred on multiple haplotype backgrounds.
确定 C9ORF72 基因中六核苷酸重复扩增的频率，该基因功能未知，但与额颞叶痴呆（FTD）和肌萎缩性侧索硬化症（ALS）有关，在澳大利亚 FTD 患者队列中，并研究与该扩增相关的临床和神经病理学表型。
我们使用重复引物 PCR 检测了一个临床确诊的 FTD 队列（n=89）和一个具有 TDP-43 病理学的额颞叶脑变性病例的神经病理学队列（FTLD-TDP，n=22）中的 C9ORF72 六核苷酸重复扩增。所有扩增阳性患者均进行了 rs3849942 基因分型，rs3849942 是先前与 FTD 和 ALS 相关的 9p21 风险单倍型的替代标志物。
在临床诊断的队列中，10%的患者检测到 C9ORF72 重复扩增，在具有早发性痴呆或 ALS 阳性家族史的患者中，这一比例上升至 29%。在扩增阳性病例中，精神病特征的患病率明显更高（56% vs. 14%）。在病理学队列中，41%的 TDP-43 阳性病例携带重复扩增，且均表现为 B 型病理学。17 名扩增阳性先证者中有 1 名是 rs3849942 的“非风险”G 等位基因纯合子。
C9ORF72 重复扩增是澳大利亚人群中 FTD 的一个相对常见的原因，尤其是在 FTD-ALS、精神病特征和家族史强的患者中。在 9p21 假定的“非风险”单倍型上检测到重复扩增表明，并非所有突变携带者都一定来自一个共同的祖先，并且表明该扩增可能发生在多个单倍型背景上。
