Expansion of the Fragile X CGG Repeat in Females with Premutation or Intermediate Alleles
Open accessAbstract
The CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR1) exhibits remarkable instability upon transmission from mothers with premutation alleles. A collaboration of 13 laboratories in eight countries was established to examine four issues concerning FMR1 CGG-repeat instability among females with premutation (approximately 55-200 repeats) and intermediate (approximately 46-60 repeats) alleles. Our central findings were as follows: (1) The smallest premutation alleles that expanded to a full mutation (>200 repeats) in one generation contained 59 repeats; sequence analysis of the 59-repeat alleles from these two females revealed no AGG interruptions within the FMR1 CGG repeat. (2) When we corrected for ascertainment and recalculated the risks of expansion to a full mutation, we found that the risks for premutation alleles with <100 repeats were lower than those previously published. (3) When we examined the possible influence of sex of offspring on transmission of a full mutation-by analysis of 567 prenatal fragile X studies of 448 mothers with premutation and full-mutation alleles-we found no significant differences in the proportion of full-mutation alleles in male or female fetuses. (4) When we examined 136 transmissions of intermediate alleles from 92 mothers with no family history of fragile X, we found that, in contrast to the instability observed in families with fragile X, most (99/136 [72.8%]) transmissions of intermediate alleles were stable. The unstable transmissions (37/136 [27.2%]) in these families included both expansions and contractions in repeat size. The instability increased with the larger intermediate alleles (19% for 49-54 repeats, 30.9% for 55-59, and 80% for 60-65 repeats). These studies should allow improved risk assessments for genetic counseling of women with premutation or intermediate-size alleles.
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The risk of premutation-to-full-mutation transition depends on CGG repeat size, with nearly 100% risk for alleles over 99 repeats.
“The risk of a PM to FM transition depends on the CGG repeat size, such that the expansion risk is nearly 100% for alleles of >99 CGG repeats (11).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [11]
Intermediate or gray-zone alleles with 45 to 54 CGG repeats are proposed precursors of premutation alleles, potentially due to meiotic instability.
“Alleles possessing between 45 and 54 CGG repeats, referred to as gray-zone or intermediate alleles, are proposed to be precursors of PM alleles, potentially due to paternal and maternal meiotic instability (11).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [11]
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- Authors
- Nolin, S. L., Brown, W. T., Glicksman, A., Houck, Jr., Gargano, A. D., Sullivan, A., Biancalana, V., Bröndum-Nielsen, K., Hjalgrim, H., Holinski-Feder, E., Kooy, F., Longshore, J., Macpherson, J., Mandel, J.-L., Matthijs, G., Rousseau, F., Steinbach, P., Väisänen, M.-L., von Koskull, H., & Sherman, S. L.
- Affiliations
- Emory University (US)
- Kennedy Center (DK)
- Greenwood Genetic Center (US)
- Wessex Regional Genetics Laboratory (GB)
- Universität Ulm (DE)
- Oulu University Hospital (FI)
- Corresponding author
- Nolin, Sarah L.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2003-02
- Volume
- 72
- Issue
- 2
- Pages
- 454-464
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC379237
- OpenAlex
- W2000064832
- Cited by
- 421
- References
- 39
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 7 · 2023: 11 · 2022: 13 · 2021: 12 · 2020: 14 · 2019: 18 · 2018: 21 · 2017: 17 · 2016: 21 · 2015: 6 · 2014: 20 · 2013: 22 · 2012: 25
- FWCI
- 10.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Helsingin ja Uudenmaan Sairaanhoitopiiri
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD29909, R01HD029909)
- 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, repeat instability, premutation, intermediate alleles, full mutation, mother-to-child transmission, offspring sex, repeat contraction, genetic counseling, risk assessment, prenatal diagnosis
- MeSH terms
- Alleles, Female, Fragile X Syndrome, Humans, Male, Mutation, Pedigree, Risk, Sex Factors, Trinucleotide Repeat Expansion, 5' Untranslated Regions, Siblings
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