AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome
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Purpose 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.Methods 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.Results We found that the presence of AGG interruptions significantly increased genetic stability, whereas specific haplotypes had a marginal association with transmission instability.Conclusion 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.
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The number of AGG interruptions in the CGG repeat correlates inversely with the risk of expansion to a full mutation in the next generation.
“A recent study (12) showed that the number of AGG interruptions present in the CGG repeats correlates inversely with the risk of expansion to a FM in the next generation.”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [12]
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- Authors
- Yrigollen, C. M., Durbin-Johnson, B., Gane, L., Nelson, D. L., Hagerman, R., Hagerman, P. J., & Tassone, F.
- Affiliations
- University of California, Davis (US)
- University of California Davis Medical Center (US)
- Baylor College of Medicine (US)
- Corresponding author
- Tassone, Flora
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 14
- Issue
- 8
- Pages
- 729-736
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC3990283
- OpenAlex
- W1985923029
- Cited by
- 179
- References
- 31
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 13 · 2023: 8 · 2022: 10 · 2021: 15 · 2020: 10 · 2019: 11 · 2018: 16 · 2017: 15 · 2016: 20 · 2015: 5 · 2014: 19 · 2013: 13 · 2012: 5
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- University of California, Davis
- National Center for Research Resources (UL1RR024146)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD040661, P30HD002274, R01HD036071)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- fragile X syndrome, FMR1 gene, CGG repeat expansion, AGG interruptions, premutation, genetic counseling, repeat instability, haplotypes, 5' untranslated region, mother-to-child transmission
- MeSH terms
- Age Factors, Alleles, Female, Fragile X Syndrome, Humans, Male, Pedigree, Risk, Trinucleotide Repeat Expansion, Penetrance, Genetic Predisposition to Disease, Fragile X Messenger Ribonucleoprotein 1
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