Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Am J Med Genet A. 2010 Oct;152A(10):2512-20. doi: 10.1002/ajmg.a.33626.
Fragile X syndrome (FXS), the most common inherited form of developmental delay, is typically caused by CGG-repeat expansion in FMR1. However, little attention has been paid to sequence variants in FMR1. Through the use of pooled-template massively parallel sequencing, we identified 130 novel FMR1 sequence variants in a population of 963 developmentally delayed males without CGG-repeat expansion mutations. Among these, we identified a novel missense change, p.R138Q, which alters a conserved residue in the nuclear localization signal of FMRP. We have also identified three promoter mutations in this population, all of which significantly reduce in vitro levels of FMR1 transcription. Additionally, we identified 10 noncoding variants of possible functional significance in the introns and 3'-untranslated region of FMR1, including two predicted splice site mutations. These findings greatly expand the catalog of known FMR1 sequence variants and suggest that FMR1 sequence variants may represent an important cause of developmental delay.
脆性 X 综合征（FXS）是最常见的遗传性发育迟缓疾病，通常由 FMR1 中的 CGG 重复扩展引起。然而，人们对 FMR1 中的序列变异关注甚少。通过使用汇集模板大规模平行测序，我们在没有 CGG 重复扩展突变的 963 名发育迟缓男性群体中鉴定出 130 种新型 FMR1 序列变异。其中，我们鉴定出一种新型错义变化 p.R138Q，它改变了 FMRP 核定位信号中的保守残基。我们还在该人群中鉴定出三种启动子突变，它们都显著降低了 FMR1 转录的体外水平。此外，我们在 FMR1 的内含子和 3'-非翻译区中鉴定出 10 种可能具有功能意义的非编码变异，包括两个预测的剪接位点突变。这些发现大大扩展了已知 FMR1 序列变异的目录，并表明 FMR1 序列变异可能是发育迟缓的一个重要原因。
