Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, Davis, CA, USA.
J Hum Genet. 2013 Aug;58(8):553-9. doi: 10.1038/jhg.2013.50. Epub 2013 Jun 6.
The CGG repeat within the premutation range in the fragile X mental retardation 1 (FMR1) gene can lead to neurodegenerative disorders and intellectual disabilities. An increase in size upon the transmission from parent to child is more likely to occur for larger alleles and without AGG interruptions. We describe the molecular structure and the transmission of an FMR1 premutation allele in a multigenerational family, identified through newborn screening for fragile X syndrome. Transmission of the premutation allele was traced through five generations in 14 of the 23 individuals who were genotyped through cascade testing. Allele size instability during transmission was observed, but no expansions to a full mutation were detected. Clinical and molecular characterizations of the participants lead to the diagnosis of fragile X-associated tremor ataxia syndrome in one subject identified as a premutation carrier. A gradual small increase in the size of the premutation allele was observed during transmission through five generations. The relative stability is likely due to the presence of two AGGs within the allele. The detection of AGG interruptions within the premutation alleles is important in genetic counseling, to better predict the risk of expansion during transmission from a premutation to a full-mutation allele.
脆性 X 智力低下 1 号基因（FMR1）中前突变范围内的 CGG 重复可导致神经退行性疾病和智力障碍。从父母传给孩子时，较大的等位基因和没有 AGG 中断更容易发生大小增加。我们描述了通过脆性 X 综合征新生儿筛查鉴定的一个多代家族中 FMR1 前突变等位基因的分子结构和传递。通过级联测试对 23 名经基因分型的个体中的 14 名进行了前突变等位基因传递的追踪。在传递过程中观察到等位基因大小不稳定，但未检测到全突变扩展。对参与者的临床和分子特征进行分析，导致对一名被鉴定为前突变携带者的患者做出脆性 X 相关震颤共济失调综合征的诊断。在前突变等位基因通过五代传递的过程中，观察到大小逐渐略有增加。相对稳定性可能归因于等位基因内存在两个 AGG。在遗传咨询中，检测前突变等位基因内的 AGG 中断对于更好地预测从前突变到全突变等位基因传递过程中的扩展风险非常重要。
