Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study.
Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study.
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DOI：
10.1016/s1474-4422(13)70210-2
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发表时间：
2013-10
期刊：
影响因子：
48
通讯作者：
Rademakers, Rosa
中科院分区：
文献类型：
--
作者：
van Blitterswijk, Marka;Dejesus-Hernandez, Mariely;Niemantsverdriet, Ellis;Murray, Melissa E.;Heckman, Michael G.;Diehl, Nancy N.;Brown, Patricia H.;Baker, Matthew C.;Finch, NiCole A.;Bauer, Peter O.;Serrano, Geidy;Beach, Thomas G.;Josephs, Keith A.;Knopman, David S.;Petersen, Ronald C.;Boeve, Bradley F.;Graff-Radford, Neill R.;Boylan, Kevin B.;Petrucelli, Leonard;Dickson, Dennis W.;Rademakers, Rosa
9号染色体开放阅读框72(C9ORF72)上的六核苷酸重复序列扩增是目前额颞叶痴呆(FTD)和运动神经元病(MND)的主要遗传原因。目前，尚不清楚扩张大小是否会影响疾病的严重程度或表型。我们在梅奥诊所和班纳太阳健康研究所获得的一组受试者中进行了一项横断面Southern印迹特征研究(Xpanize-72)。所有受试者均携带C9ORF72的GGGGCC重复扩增，额叶皮质、小脑和/或血液中均可获得高质量的DNA。Southern杂交技术和密度计量学被用来估计最丰富的扩展物种的重复大小。组织间重复大小的比较使用Wilcoxon秩和和Wilcoxon符号秩和检验，疾病亚组之间的重复大小比较使用Kruskal-Wallis秩和检验。使用Spearman相关性检验评估重复大小与发病年龄和收集年龄的相关性；而使用Cox比例风险回归模型检验重复大小与疾病发病后生存率之间的关联。我们的队列包括84名C9ORF72扩张型携带者，其中FTD患者35例，FTD/MND患者16例，MND患者30例，正常对照3例。我们重点分析了三个主要组织亚群：额叶皮质(41名受试者[21名FTD，11名FTD/MND，9名MND])，小脑(40名受试者[20名FTD，12名FTD/MND，8名MND])和50名受试者(50名受试者[15名FTD，9名FTD/MND，23名MND，3名未受影响的扩张型携带者])。小脑的重复长度(中位数12.3kb[~1667个重复单位]，IQR 11.1~14.3)显著小于额叶皮质(中位数33.8kb[~5250个重复单位]，IQR 23.5~44.1，p<；0.0001)或血液(中位数18.6kb[~2717个重复单位]，IQR 13.9~28.1，p=0.0002)。在这些组织中，疾病亚组之间的重复长度差异无统计学意义(小脑p=0.96，额叶p=0.27，血液p=0.10)。在FTD患者的额叶皮质，重复长度与发病年龄(r=0.63，p=0.003)和采集年龄(r=0.58，p=0.006)相关；在小脑和血液中未检测到这种相关性。最后，仅在小脑，重复长度大于1467个重复单位(第25百分位数，HR 3·27，95%CI 1·34-7·95，p=0.009)的患者发病后的存活率较差：扩张时间较长组的中位生存期为4·8年(IQR 3·0-7·4)，而扩张较小的组为7.4年(IQR 6·3-10·9)。在小脑、额叶皮质和血液中观察到重复大小有很大差异；小脑中相对较长的重复大小是一个重要的生存劣势。我们的发现表明，扩张的大小确实会影响疾病的严重程度，这可能与遗传咨询有关。
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are currently the major genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). Presently, it is unknown whether expansion size affects disease severity or phenotypes. We performed a cross-sectional Southern blot characterization study (Xpansize-72) in a cohort of subjects obtained at the Mayo Clinic and Banner Sun Health Research Institute. All subjects carried GGGGCC repeat expansions in C9ORF72, and high quality DNA was available from the frontal cortex, cerebellum and/or blood. Southern blotting techniques and densitometry were employed to estimate the repeat size of the most abundant expansion species. Comparisons of repeat sizes between tissues were made using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. The association of repeat size with age at onset and age at collection was evaluated using a Spearman’s test of correlation; whereas the association between repeat size and survival after disease onset was examined using Cox proportional hazards regression models. Our cohort consisted of 84 C9ORF72 expansion carriers, including FTD patients (n=35), FTD/MND patients (n=16), MND patients (n=30), and unaffected subjects (n=3). We focused our analysis on three major tissue subgroups: frontal cortex (41 subjects [21 FTD, 11 FTD/MND, 9 MND]), cerebellum (40 subjects [20 FTD, 12 FTD/MND, 8 MND]), and blood (50 subjects [15 FTD, 9 FTD/MND, 23 MND, 3 unaffected expansion carriers]). Repeat lengths in the cerebellum were significantly smaller (median 12·3 kb [~1667 repeat units], IQR 11·1–14·3) than in the frontal cortex (median 33·8 kb [~5250 repeat units], IQR 23·5–44·9, p<0·0001), or in blood (median 18·6 kb [~2717 repeat units], IQR 13·9–28·1, p=0·0002). Within these tissues, there was no significant difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of FTD patients, repeat length correlated with age at onset (r=0·63, p=0·003) and age at collection (r=0·58, p=0·006); this correlation was not detected in the cerebellum or blood. Finally, only in the cerebellum, survival after disease onset was poorer in patients from our overall cohort with repeat lengths greater than 1467 repeat units (25th percentile, HR 3·27, 95% CI 1·34–7·95, p=0·009): the median survival was 4·8 years (IQR 3·0–7·4) in the group with longer expansions versus 7·4 years (IQR 6·3–10·9) in the group with smaller expansions. Substantial variation in repeat size is observed between cerebellum, frontal cortex, and blood; relatively long repeat sizes in the cerebellum confer an important survival disadvantage. Our findings indicate that expansion size does affect disease severity, which could be relevant for genetic counseling.