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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Journal of Neurodevelopmental Disorders 1/2014

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

Zeitschrift:
Journal of Neurodevelopmental Disorders > Ausgabe 1/2014
Autoren:
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
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1866-1955-6-24) contains supplementary material, which is available to authorized users.

Competing interests

CMY, LM, BDJ, MN, JG, AM, RP, LZ, DB, AR, and BF have no disclosures. FT has received funds from Roche. EBK has received support from Asuragen, Inc. in the development of control samples for FMR1 testing. GJL and AH have stock options in Asuragen, Inc.

Authors’ contributions

CMY contributed to the design experiments, performed experiments, helped with data analysis, and prepared the manuscript. LM, AM, and EBK provided samples, provided critical review of the manuscript. BDJ performed all statistical analyses and provided critical review of the manuscript. MN, JG, RP, and LZ performed experiments and provided critical review of the manuscript. DB, ARD, and BF contributed genetic counseling related text to the manuscript and provided critical review of the manuscript. GL and AH provided critical review of the manuscript. FT conceived of the study, provided samples, designed the experiments, and prepared the manuscript. All authors have read and approved the final manuscript.

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.
Zusatzmaterial
Additional file 1: Table S1: Participants included in the analysis. Table S2. Predicted risk of expansion to a full mutation using total CGG length and AGGs. Table S3. Summary of 710 observed transmissions from premutation carrier mothers. Table S4. Binomial logistic regression analysis of instability in premutation mothers. (DOCX 73 KB)
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Additional file 2: Figure S1: Percent of transmissions of maternal premutation alleles that resulted in a full mutation child. The observed frequency of children with a full mutation grouped by 0 (black line), 1 (red line), and 2 or 3 (green line) AGG interruptions in the maternal premutation allele increases with increased CGG size and decreases with increased number of AGG interruptions. Data were corrected for mothers with multiple children. (TIFF 1 MB)
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Additional file 3: Figure S2: Instability measures of maternal intermediate and premutation alleles. Instability of the CGG repeat allele increases with the total length of the allele. The proportion of alleles with 0 (black), 1 (red), and 2 or 3 (green) AGG interruptions, that are unstable, changes as alleles become more unstable and begin expanding to a full mutation (0 and 1 AGG interruptions). A higher proportion of alleles with 2 or 3 AGG interruptions are observed for longer repeats as they do not expand to a full mutation. (TIFF 1 MB)
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