Terracciano Alessandra, Pomponi Maria Grazia, Marino Grazia Maria Elisabetta, Chiurazzi Pietro, Rinaldi Maria Michela, Dobosz Marina, Neri Giovanni
Institute of Medical Genetics, Catholic University, Rome, Italy.
Eur J Hum Genet. 2004 Apr;12(4):333-6. doi: 10.1038/sj.ejhg.5201154.
Fragile X syndrome is due to an expanded CGG repeat in the 5' UTR of the FMR1 gene. According to repeat size, we distinguish four allele categories: normal (<40 CGG), intermediate (46-60 CGG), premutated (55-200 CGG) and full mutated (>200 CGG). However, the boundaries among these categories are unclear, making it difficult to classify unstable alleles and to estimate the risk of expansion. We report a family with a proband, carrying a methylated full mutation with an amplification of 1.2 kb. PCR analysis demonstrated two alleles of 29 and 61 CGGs in the mother. Sequencing of the 61 CGG allele showed no AGG interruptions. Both mother's sisters had two alleles of 31 and 44 CGGs, and the daughter of one of these had two alleles of 22 and 44 repeats, demonstrating stable transmission of the 44 CGG allele. The maternal grandfather was deceased, but haplotype reconstruction using markers DXS548 and FRAXAC1 demonstrated that he was carrier of the premutated allele. Furthermore, molecular analysis confirmed the same paternity with a probability of 99.79% for all the three sisters. According to these findings, it is likely that the maternal grandfather carried the 44 CGG allele, showing unstable transmission, given that it expanded first to 61 CGGs in one daughter, and then to full mutation in her child. Although we cannot exclude paternal mosaicism, it is likely that a rare event of progression from an intermediate to a premutated and on to a full mutated allele occurred in this family over two generations.
脆性X综合征是由于FMR1基因5'非翻译区的CGG重复序列扩增所致。根据重复序列的大小，我们区分出四种等位基因类别：正常（<40个CGG）、中间型（46 - 60个CGG）、前突变型（55 - 200个CGG）和完全突变型（>200个CGG）。然而，这些类别之间的界限并不清晰，这使得不稳定等位基因的分类以及扩增风险的评估变得困难。我们报告了一个家系，先证者携带一个甲基化的完全突变，扩增片段为1.2 kb。PCR分析显示母亲有两个等位基因，分别为29和61个CGG。对61个CGG等位基因进行测序未发现AGG中断。母亲的两个姐妹都有两个等位基因，分别为31和44个CGG，其中一个姐妹的女儿有两个等位基因，分别为22和44个重复序列，表明44个CGG等位基因能够稳定传递。外祖父已去世，但使用标记DXS548和FRAXAC1进行单倍型重建表明他是前突变等位基因的携带者。此外，分子分析证实这三个姐妹的父系相同概率为99.79%。根据这些发现，外祖父很可能携带44个CGG等位基因，其传递不稳定，因为它首先在一个女儿中扩增到61个CGG，然后在她的孩子中发展为完全突变。虽然我们不能排除父系嵌合体的可能性，但在这个家系中，很可能在两代人中发生了从中间型等位基因罕见地发展为前突变型等位基因，进而发展为完全突变型等位基因的情况。
