美国纽约西奈山伊坎医学院Andrew J. Sharp团队近期取得重要工作进展，他们开展了一项关于富含甲基化GC重复序列的全现象关联研究，揭示出AFF3中的GCC重复序列扩增与智力残疾有关。相关研究成果2024年9月23日在线发表于《自然—遗传学》杂志上。

据介绍，富含GC的串联重复扩增（TRE）通常与DNA甲基化、基因沉默和叶酸敏感脆弱位点有关，是几种先天性和迟发性疾病的基础。

通过DNA甲基化分析和串联重复基因分型的结合，研究人员鉴定了24种甲基化TRE，并使用来自英国生物库的168641名个体的全表型关联研究，研究了它们对人类性状的影响，确定了156种重要的TRE-性状关联，涉及17种不同的TRE。

其中，AFF3启动子中GCC的扩增与完成中等教育的概率降低2.4倍有关，其影响大小与几种复发性致病性微缺失相当。在一个由6371名疑似遗传病因的神经发育问题先证者组成的队列中，研究人员观察到与对照组相比，AFF3扩增显著增加。由于人群患病率至少比导致脆性X综合征的TRE高五倍，AFF3扩增是神经发育迟缓的主要原因。

附：英文原文

Title: A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability

Author: Jadhav, Bharati, Garg, Paras, van Vugt, Joke J. F. A., Ibanez, Kristina, Gagliardi, Delia, Lee, William, Shadrina, Mariya, Mokveld, Tom, Dolzhenko, Egor, Martin-Trujillo, Alejandro, Gies, Scott J., Altman, Gabrielle, Rocca, Clarissa, Barbosa, Mafalda, Jain, Miten, Lahiri, Nayana, Lachlan, Katherine, Houlden, Henry, Paten, Benedict, Veldink, Jan, Tucci, Arianna, Sharp, Andrew J.

Issue&Volume: 2024-09-23

Abstract: GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE–trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay.

DOI: 10.1038/s41588-024-01917-1

Source: https://www.nature.com/articles/s41588-024-01917-1