Expansion to full mutation of a FMR1 intermediate allele over two generations
| Autor: | Grazia Maria Elisabetta Marino, Giovanni Neri, Maria Grazia Pomponi, Marina Dobosz, Alessandra Terracciano, Maria Michela Rinaldi, Pietro Chiurazzi |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Proband congenital hereditary and neonatal diseases and abnormalities media_common.quotation_subject Fixed allele Nerve Tissue Proteins Paternity Biology Polymerase Chain Reaction Fragile X Mental Retardation Protein Genetics medicine Humans Allele Child Alleles Genetics (clinical) media_common Daughter Genetic Carrier Screening Haplotype RNA-Binding Proteins medicine.disease FMR1 Pedigree Fragile X syndrome Blotting Southern Mutation Mutation (genetic algorithm) Female |
| Zdroj: | European Journal of Human Genetics. 12:333-336 |
| ISSN: | 1476-5438 1018-4813 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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