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Open Access 01-12-2014 | Research

AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission

Authors: Carolyn M Yrigollen, Loreto Martorell, Blythe Durbin-Johnson, Montserrat Naudo, Jordi Genoves, Alessandra Murgia, Roberta Polli, Lili Zhou, Deborah Barbouth, Abigail Rupchock, Brenda Finucane, Gary J Latham, Andrew Hadd, Elizabeth Berry-Kravis, Flora Tassone

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2014

Abstract

Background

The presence of AGG interruptions in the CGG repeat locus of the fragile X mental retardation 1 (FMR1) gene decreases the instability of the allele during transmission from parent to child, and decreases the risk of expansion of a premutation allele to a full mutation allele (the predominant cause of fragile X syndrome) during maternal transmission.

Methods

To strengthen recent findings on the utility of AGG interruptions in predicting instability or expansion to a full mutation of FMR1 CGG repeat alleles, we assessed the outcomes of 108 intermediate (also named gray zone) and 710 premutation alleles that were transmitted from parent to child, and collected from four international clinical sites. We have used the results to revise our initial model that predicted the risk of a maternal premutation allele expanding to a full mutation during transmission and to test the effect of AGG interruptions on the magnitude of expanded allele instability of intermediate or premutation alleles that did not expand to a full mutation.

Results

Consistent with previous studies, the number of AGG triplets that interrupts the CGG repeat locus was found to influence the risk of allele instability, including expansion to a full mutation. The total length of the CGG repeat allele remains the best predictor of instability or expansion to a full mutation, but the number of AGG interruptions and, to a much lesser degree, maternal age are also factors when considering the risk of transmission of the premutation allele to a full mutation.

Conclusions

Our findings demonstrate that a model with total CGG length, number of AGG interruptions, and maternal age is recommended for calculating the risk of expansion to a full mutation during maternal transmission. Taken together, the results of this study provide relevant information for the genetic counseling of female premutation carriers, and improve the current predictive models which calculate risk of expansion to a full mutation using only total CGG repeat length.

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Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG, Warren ST, Oostra BA, Nelson DL, Caskey CT: Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991, 67: 1047-1058.PubMedCrossRef

Oberle I, Rousseau F, Heitz D, Kretz C, Devys D, Hanauer A, Boue J, Bertheas MF, Mandel JL: Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science. 1991, 252: 1097-1102.PubMedCrossRef

Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, Eussen BE, van Ommen GJB, Blonden LAJ, Riggins GJ, Chastain JL, Kunst CB, Galjaard H, Caskey CT, Nelson DL, Oostra BA, Warren ST: Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991, 65: 905-914.PubMedCrossRef

Eichler EE, Hammond HA, Macpherson JN, Ward PA, Nelson DL: Population survey of the human FMR1 CGG repeat substructure suggests biased polarity for the loss of AGG interruptions. Human Mole Genet. 1995, 4: 2199-2208.CrossRef

Eichler EE, Holden JJ, Popovich BW, Reiss AL, Snow K, Thibodeau SN, Richards CS, Ward PA, Nelson DL: Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nature Genet. 1994, 8: 88-94.PubMedCrossRef

Snow K, Tester DJ, Kruckeberg KE, Schaid DJ, Thibodeau SN: Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation. Human Mole Genet. 1994, 3: 1543-1551.CrossRef

Zhong N, Yang W, Dobkin C, Brown WT: Fragile X gene instability: anchoring AGGs and linked microsatellites. Am J Human Genet. 1995, 57: 351-361.

Kunst CB, Warren ST: Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell. 1994, 77: 853-861.PubMedCrossRef

Gacy AM, Goellner G, Juranic N, Macura S, McMurray CT: Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell. 1995, 81: 533-540.PubMedCrossRef

10.

Yrigollen CM, Durbin-Johnson B, Gane L, Nelson DL, Hagerman R, Hagerman PJ, Tassone F: AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. Genet Med. 2012, 14: 729-736.PubMedPubMedCentralCrossRef

11.

Nolin SL, Sah S, Glicksman A, Sherman SL, Allen E, Berry-Kravis E, Tassone F, Yrigollen C, Cronister A, Jodah M, Ersalesi N, Dobkin C, Brown WT, Shroff R, Latham GJ, Hadd AG: Fragile X AGG analysis provides new risk predictions for 45–69 repeat alleles. Am J Med Genet A. 2013, 161: 771-778.CrossRef

12.

Yrigollen CM, Tassone F, Durbin-Johnson B, Tassone F: The role of AGG interruptions in the transcription of FMR1 premutation alleles. PloS one. 2011, 6: e21728-PubMedPubMedCentralCrossRef

13.

Peprah E, He W, Allen E, Oliver T, Boyne A, Sherman SL: Examination of FMR1 transcript and protein levels among 74 premutation carriers. J Human Genet. 2010, 55: 66-68.CrossRef

14.

Ludwig AL, Raske C, Tassone F, Garcia-Arocena D, Hershey JW, Hagerman PJ: Translation of the FMR1 mRNA is not influenced by AGG interruptions. Nucleic Acids Res. 2009, 37: 6896-6904.PubMedPubMedCentralCrossRef

15.

Tassone F, Beilina A, Carosi C, Albertosi S, Bagni C, Li L, Glover K, Bentley D, Hagerman PJ: Elevated FMR1 mRNA in premutation carriers is due to increased transcription. RNA. 2007, 13: 555-562.PubMedPubMedCentralCrossRef

16.

Peprah E: Fragile X syndrome: the FMR1 CGG repeat distribution among world populations. Ann Hum Genet. 2012, 76: 178-191.PubMedPubMedCentralCrossRef

17.

Chen L, Hadd A, Sah S, Filipovic-Sadic S, Krosting J, Sekinger E, Pan R, Hagerman PJ, Stenzel TT, Tassone F, Latham GJ: An information-rich CGG repeat primed PCR that detects the full range of fragile X expanded alleles and minimizes the need for southern blot analysis. J Mol Diagn. 2010, 12: 589-600.PubMedPubMedCentralCrossRef

18.

Tassone F, Pan R, Amiri K, Taylor AK, Hagerman PJ: A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile X (FMR1) gene in newborn and high-risk populations. J Mol Diagn. 2008, 10: 43-49.PubMedPubMedCentralCrossRef

19.

Filipovic-Sadic S, Sah S, Chen L, Krosting J, Sekinger E, Zhang W, Hagerman PJ, Stenzel TT, Hadd AG, Latham GJ, Tassone F: A novel FMR1 PCR method for the routine detection of low abundance expanded alleles and full mutations in fragile X syndrome. Clin Chem. 2010, 56: 399-408.PubMedPubMedCentral

20.

Tassone F, Iong KP, Tong TH, Lo J, Gane LW, Berry-Kravis E, Nguyen D, Mu LY, Laffin J, Bailey DB, Hagerman RJ: FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med. 2012, 4: 100-PubMedPubMedCentralCrossRef

21.

Yrigollen CM, Mendoza-Morales G, Hagerman R, Tassone F: Transmission of an FMR1 premutation allele in a large family identified through newborn screening: the role of AGG interruptions. J Hum Genet. 2013, 58: 553-559.PubMedPubMedCentralCrossRef

22.

Lokanga RA, Zhao XN, Usdin K: The mismatch repair protein MSH2 is rate limiting for repeat expansion in a fragile X premutation mouse model. Human Mut. 2013, 35: 129-136.CrossRef

23.

Team RC: A language and environment for statistical computing. 2013, Vienna, Austria: R Foundation for Statistical Computing, Available: http://www.R-project.org/

24.

Mornet E, Jokic M, Bogyo A, Tejada I, Deluchat C, Boue J, Boue A: Affected sibs with fragile X syndrome exhibit an age-dependent decrease in the size of the fragile X full mutation. Clin Gen. 1993, 43: 157-159.CrossRef

25.

Ashley-Koch AE, Robinson H, Glicksman AE, Nolin SL, Schwartz CE, Brown WT, Turner G, Sherman SL: Examination of factors associated with instability of the FMR1 CGG repeat. Am J Human Genet. 1998, 63: 776-785.CrossRef

26.

Nolin SL, Glicksman A, Ding X, Ersalesi N, Brown WT, Sherman SL, Dobkin C: Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenatal Diagn. 2011, 31: 925-931.CrossRef

27.

McMurray CT: Mechanisms of trinucleotide repeat instability during human development. Nature Rev Genet. 2010, 11: 786-799.PubMedPubMedCentralCrossRef

28.

Pearson CE, Nichol Edamura K, Cleary JD: Repeat instability: mechanisms of dynamic mutations. Nature Rev Genet. 2005, 6: 729-742.PubMedCrossRef

Title: AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission
Authors: Carolyn M Yrigollen
Loreto Martorell
Blythe Durbin-Johnson
Montserrat Naudo
Jordi Genoves
Alessandra Murgia
Roberta Polli
Lili Zhou
Deborah Barbouth
Abigail Rupchock
Brenda Finucane
Gary J Latham
Andrew Hadd
Elizabeth Berry-Kravis
Flora Tassone
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Journal of Neurodevelopmental Disorders / Issue 1/2014
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI: https://doi.org/10.1186/1866-1955-6-24

ACC 2024 Congress

Springer Medicine

AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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