Department of Biochemistry and Molecular Medicine, University of California-Davis School of Medicine, Davis, California, USA.
Genet Med. 2012 Aug;14(8):729-36. doi: 10.1038/gim.2012.34. Epub 2012 Apr 12.
The ability to accurately predict the likelihood of expansion of the CGG repeats in the FMR1 gene to a full mutation is of critical importance for genetic counseling of women who are carriers of premutation alleles (55-200 CGG repeats) and who are weighing the risk of having a child with fragile X syndrome. The presence of AGG interruptions within the CGG repeat tract is thought to decrease the likelihood of expansion to a full mutation during transmission, thereby reducing risk, although their contribution has not been quantified.
We retrospectively analyzed 267 premutation alleles for number and position of AGG interruptions, length of pure CGG repeats, and CGG repeat lengths present in the offspring of the maternal transmissions. In addition, we determined the haplotypes of four markers flanking the 5'-UTR locus in the premutation mothers.
We found that the presence of AGG interruptions significantly increased genetic stability, whereas specific haplotypes had a marginal association with transmission instability.
The presence of AGG interruptions reduced the risk of transmission of a full mutation for all maternal (premutation) repeat lengths below ~100 CGG repeats, with a differential risk (0 vs. 2 AGG) exceeding 60% for alleles in the 70- to 80-CGG repeat range.
准确预测脆性 X 综合征前突变等位基因（55-200 CGG 重复）携带者生育脆性 X 综合征患儿风险的能力，对于遗传咨询至关重要。在 CGG 重复序列中存在 AGG 中断，被认为会降低在传递过程中扩展为完全突变的可能性，从而降低风险，尽管其贡献尚未量化。
我们回顾性分析了 267 个前突变等位基因的 AGG 中断数量和位置、纯 CGG 重复长度以及母体传递后代的 CGG 重复长度。此外，我们还确定了前突变母亲 5'-UTR 基因座侧翼的四个标记的单倍型。
我们发现 AGG 中断的存在显著增加了遗传稳定性，而特定的单倍型与传递不稳定有一定的关联。
AGG 中断的存在降低了所有低于约 100 CGG 重复的母体（前突变）重复长度的完全突变传递风险，在 70-80 CGG 重复范围内的等位基因中，风险差异（0 与 2 AGG）超过 60%。
