Format

Send to

Choose Destination
See comment in PubMed Commons below
Eur J Hum Genet. 2004 Apr;12(4):333-6.

Expansion to full mutation of a FMR1 intermediate allele over two generations.

Author information

1
Institute of Medical Genetics, Catholic University, Rome, Italy.

Abstract

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.

PMID:
14735162
DOI:
10.1038/sj.ejhg.5201154
[Indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group
    Loading ...
    Support Center