Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Nat Genet. 2024 Nov;56(11):2322-2332. doi: 10.1038/s41588-024-01917-1. Epub 2024 Sep 23.
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.
富含 GC 的串联重复扩展（TREs）通常与 DNA 甲基化、基因沉默和叶酸敏感脆性位点有关，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相结合，我们在来自英国生物银行的 168641 名个体中进行了全表型关联研究，鉴定了 24 个甲基化 TRE，并研究了它们对人类特征的影响，确定了 17 个不同 TRE 与 156 个显著的 TRE-性状关联。其中，AFF3 启动子中的 GCC 扩展与完成中等教育的概率降低 2.4 倍有关，其效应大小与几种常见的致病性微缺失相当。在一个由 6371 名有疑似遗传病因的神经发育问题先证者组成的队列中，与对照组相比，我们观察到 AFF3 扩展的显著富集。AFF3 扩展的人群患病率至少是导致脆性 X 综合征的 TRE 的五倍，代表了神经发育迟缓的主要原因。
