BACKGROUND Fragile X syndrome (FXS) is a monogenic disorder and a common cause of intellectual disability (ID). Up to now, very few pathological variants other than the typical CGG-repeat expansion have been reported in the FMR1 gene. METHODS A panel of 56 intellectual disability (ID) genes including the FMR1 gene was sequenced in a cohort of 300 patients with unexplained ID. To determine the effect of a new FMR1 variant, total RNA from peripheral blood cells was reverse transcribed, amplified by polymerase chain reaction and sequenced. RESULTS We report a novel G to A point variant (c.801G>A) located at the last nucleotide of exon 8 in the FMR1 gene in one patient with ID. Direct sequencing of the RT-PCR products revealed that the transcript from the allele with G to A variant skips exon 8 entirely, resulting in a joining of exons 7 and 9. Skipping of exon 8 may result in an abnormal FMR1 protein (FMRP), which removes the highly conserved region that encoding the KH1 domain of FMRP. CONCLUSIONS This report describes for the first time that a synonymous variant in the FMR1 gene is associated with an error in mRNA processing, leading preferentially to the production of an aberrant transcript without exon 8. This splice variant was associated with an unspecific clinical presentation, suggesting the need for more detailed investigation of silent variants in ID patients with a large spectrum of phenotypes.

中文翻译：

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由于同义变异，人类FMR1的KH1结构域丢失会导致整体发育迟缓。

背景技术脆性X综合征（FXS）是一种单基因疾病，并且是智力障碍（ID）的常见原因。到目前为止，FMR1基因中除了典型的CGG重复扩增外，几乎没有其他病理学变异。方法在300名患有无法解释的ID的患者队列中对包括FMR1基因在内的56个智力障碍（ID）基因进行了测序。为了确定新的FMR1变体的作用，将来自外周血细胞的总RNA反转录，通过聚合酶链反应扩增并测序。结果我们报道了一个ID患者的FMR1基因外显子8的最后一个核苷酸处的一个新的G点到A点变异（c.801G> A）。RT-PCR产物的直接测序表明，从具有G到A的等位基因的转录本完全跳过了外显子8，导致外显子7和9的连接。跳过外显子8可能会导致FMR1蛋白（FMRP）异常，从而删除了编码FMRP KH1域的高度保守的区域。结论本报告首次描述FMR1基因的同义变体与mRNA加工错误有关，从而优先导致产生没有外显子8的异常转录本。该剪接变体与非特异性临床表现相关，提示需要对具有大量表型的ID患者的沉默变异进行更详细的研究。