美国纽塔里敦再生元遗传学中心Sahar Gelfman小组取得一项新突破。他们的研究认为人口规模重复扩张阐明疾病风险和脑萎缩。相关论文于2026年4月8日发表在《自然》杂志上。

在这里，课题组通过分析1020833个不同样本中37个疾病相关STR基因座的重复序列长度，对致病性重复扩增进行了人群规模的调查，主题是短读测序全外显子组和全基因组数据。与之前的研究结果一致，该课题组发现大多数位点的致病重复序列的频率高于相应疾病的患病率。重复长度与7671个二元特征的关联捕获了已知的位点-性状关联，包括HTT和亨廷顿氏病，DMPK和肌强直性疾病，C9orf72和运动神经元疾病等。

最后，小组发现，甚至在疾病诊断之前，几个位点的重复扩增与特定疾病相关区域的神经丝轻链（NfL）水平升高和脑容量损失密切相关。例如，HTT扩增的携带者壳核体积损失22.1%，CACNA1A扩增的携带者小脑体积损失24.6%。这些观察结果表明，脑容量减少和NfL水平升高都发生在疾病诊断之前。本研究展示了从不同人群规模队列的短读测序数据中描述重复扩增的主题及其在流行病学和临床生物标志物开发中的应用。

据了解，短串联重复序列（STR）的致病性扩增导致70多种神经系统疾病。

附：英文原文

Title: Population-scale repeat expansions elucidate disease risk and brain atrophy

Author: Pounraja, Vijay Kumar, Sul, Jae Hoon, Herman, Joseph, OKeeffe, Sean, Rajagopal, Veera, Bai, Xiaodong, Kessler, Michael D., Parikshak, Neelroop, Landheer, Karl, Zhang, Xingmin, Yu, Sean, Zhang, Lance, LeBlanc, Michelle G., Rico-Varela, Jennifer, Grau, Frederic, Wolf, Sarah, Sundaramoorthy, Sriramkumar, Sepehrband, Farshid, Stahl, Eli A., Huo, Yuda, Ahmed, Mohsin, Croll, Susan, Salerno, William, Overton, John D., Marchini, Jonathan, Reid, Jeffrey, Lotta, Luca A., Baras, Aris, Abecasis, Goncalo R., Coppola, Giovanni, Gelfman, Sahar

Issue&Volume: 2026-04-08

Abstract: Pathogenic expansions of short tandem repeats (STRs) cause over 70 neurological diseases1,2,3. Here we performed a population-scale survey of pathogenic repeat expansions by analysing repeat length in 37 disease-associated STR loci in a diverse set of 1,020,833 samples using short-read sequencing whole-exome and whole-genome data. Consistent with previous findings, we found that the frequency of pathogenic repeats is higher than the prevalence of corresponding diseases for most loci4,5. Associations of repeat length with 7,671 binary traits captured known locus–trait associations, including HTT and Huntington’s disease, DMPK and myotonic disorders and C9orf72 and motor neuron disease, among others. Finally, we found that, even before disease diagnosis, repeat expansions in several loci strongly associate with increased levels of neurofilament light chain (NfL) and a loss of brain volume in specific disease-associated regions. For example, carriers of HTT expansions exhibited a 22.1% loss of putamen volume, and carriers of CACNA1A expansions showed a 24.6% loss of cerebellar volume. These observations suggest that both decreased brain volumes and increased NfL levels occur earlier than disease diagnosis. This study demonstrates the use of characterizing repeat expansions from short-read sequencing data in diverse population-scale cohorts and its application to epidemiology and clinical biomarker development.

DOI: 10.1038/s41586-026-10345-6

Source: https://www.nature.com/articles/s41586-026-10345-6