Center for Applied Human Molecular Genetics, The Kennedy Center, Glostrup, Denmark.
Eur J Hum Genet. 2011 Apr;19(4):489-91. doi: 10.1038/ejhg.2010.223. Epub 2011 Jan 26.
Fragile X syndrome is a common cause of inherited intellectual disability. It is caused by lack of the FMR1 gene product FMRP. The most frequent cause is the expansion of a CGG repeat located in the 5'UTR of FMR1. Alleles with 200 or more repeats become hypermethylated and transcriptionally silent. Only few patients with intragenic point mutations in FMR1 have been reported and, currently, routine analysis of patients referred for fragile X syndrome includes solely analysis for repeat expansion and methylation status. We identified a substitution in exon 2 of FMR1, c.80C>A, causing a nonsense mutation p.Ser27X, in a patient with classical clinical symptoms of fragile X syndrome. The mother who carried the mutation in heterozygous form presented with mild intellectual impairment. We conclude that further studies including western blot and DNA sequence analysis of the FMR1 gene should be performed in patients with typical symptoms of fragile X syndrome in whom no CGG repeat expansion is detected.
脆性 X 综合征是一种常见的遗传性智力障碍。它是由 FMR1 基因产物 FMRP 的缺失引起的。最常见的原因是位于 FMR1 5'UTR 中的 CGG 重复序列的扩展。重复次数达到 200 次或更多的等位基因会发生超甲基化和转录沉默。目前仅报道了少数 FMR1 基因内点突变的患者，目前，对脆性 X 综合征患者的常规分析仅包括重复扩展和甲基化状态的分析。我们在一个具有典型脆性 X 综合征临床症状的患者中鉴定出 FMR1 外显子 2 中的 c.80C>A 取代，导致无意义突变 p.Ser27X。携带该突变的母亲呈杂合形式，表现为轻度智力障碍。我们得出结论，对于无 CGG 重复扩展但具有典型脆性 X 综合征症状的患者，应进一步进行包括 Western blot 和 FMR1 基因突变的 DNA 序列分析。
