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. 2012 Aug;14(8):729-36.
doi: 10.1038/gim.2012.34. Epub 2012 Apr 12.

AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome

Carolyn M Yrigollen  1 , Blythe Durbin-Johnson, Louise Gane, David L Nelson, Randi Hagerman, Paul J Hagerman, Flora Tassone
Affiliations

AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome

Carolyn M Yrigollen et al. Genet Med. 2012 Aug.

Abstract

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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Conflict of interest statement

Conflicts of interest

Drs. Tassone and P Hagerman are non-paid collaborators with Asuragen, Inc. They have a patent for the detection of FMR1 allele size and category using the CGG linker PCR-based approach. Dr. P Hagerman is currently collaborating with Pacific Biosciences on an FMR1 sequencing effort. Dr. R Hagerman has received funding for treatment trials in FXS or autism from Novartis, Roche, Seaside Therapeutics, Curemark, Forest Pharmaceuticals and the National Fragile X Foundation.

Figures

Figure 1
Figure 1
Examples of electropherogram patterns of CGG-repeat-containing PCR products for two female premutation carriers, one with 2 AGG interruptions in the normal allele (29 CGG repeats) and no AGG in the premutation allele (71 CGG repeats) (A) and one with 1 AGG interruption in the normal (30 CGG repeats) and 2 AGG interruptions in the premutation allele (73 CGG repeats) (B). The corresponding pedigrees are provided for each subject, illustrating the effect of the presence of AGGs on transmission to a premutation (2 AGGs present in the maternal allele, 73 CGG) or to a full mutation (0 AGG present in the maternal allele, 71 CGG) offspring. In both females, the normal and the premutation allele lengths, shown as serial peaks, are illustrated at the bottom of each electrophoregram as a black line. Location and number of the AGG interruptions for each allele were determined as described in the Supplementary Appendix. A diagram showing the total CGG-repeat length (inclusive of AGGs), pure CGG-repeat length, and the AGG-containing CGG-repeat “tail” within an FMR1 premutation allele is also shown.
Figure 2
Figure 2
Risk of expansion to a full mutation during maternal transmission. (A) Percent of alleles that expanded to a full mutation as a function of total CGG repeat length, for 0 (solid circle), 1 (gray triangles), or 2 (gray squares) AGG interruptions. (B) Percent full mutation expansions as a function of pure CGG repeat length within alleles that have either 0, 1, or 2 AGGs.
Figure 3
Figure 3
Predicted risk of expansion during transmission by maternal total CGG repeat and AGG interruptions. Risk of expansion decreases when the number of AGG interruptions increases, for the same total CGG repeat length. The differential risk between one and two AGG interruptions is highest between 75 and 80 total CGG repeats.
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References

    1. Till SM. The developmental roles of FMRP. Biochem Soc Trans. 2010 Apr;38(2):507–510. - PubMed
    1. Oostra BA, Willemsen R. FMR1: a gene with three faces. Biochim Biophys Acta. 2009 Jun;1790(6):467–477. - PMC - PubMed
    1. Rooms L, Kooy RF. Advances in understanding fragile X syndrome and related disorders. Curr Opin Pediatr. 2011 Dec;23(6):601–606. - PubMed
    1. Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005 Oct;7(8):584–587. - PMC - PubMed
    1. Hagerman RJ, Berry-Kravis E, Kaufmann WE, et al. Advances in the treatment of fragile X syndrome. Pediatrics. 2009 Jan;123(1):378–390. - PMC - PubMed

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