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

Yrigollen CM, Martorell L, Durbin-Johnson B, Naudo M, Genoves J, Murgia A, Polli R, Zhou L, Barbouth D, Rupchock A, Finucane B, Latham GJ, Hadd A, Berry-Kravis E, Tassone F - J Neurodev Disord (2014)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, 2700 Stockton Blvd., Suite 2102, Sacramento, CA 95817, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Predicted risk of a maternal premutation allele expanding to a full mutation during transmission. Risk calculated using total CGG length and separately for 0, 1, and 2 or 3 AGG interruptions (black, red, and green lines, respectively) in 710 transmissions. The difference in the predicted risk of expansion to a full mutation between alleles with 0 and 2 or 3 AGG interruptions is shown as a blue line.
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Figure 1: Predicted risk of a maternal premutation allele expanding to a full mutation during transmission. Risk calculated using total CGG length and separately for 0, 1, and 2 or 3 AGG interruptions (black, red, and green lines, respectively) in 710 transmissions. The difference in the predicted risk of expansion to a full mutation between alleles with 0 and 2 or 3 AGG interruptions is shown as a blue line.

Mentions: The reported predicted risks of a premutation allele expanding to a full mutation allele during maternal transmission are based on the analyses of 710 transmission events from 525 premutation carrier mothers using CGG total length and number of AGG interruptions as variables (FigureĀ 1, Additional file 1: Table S2). A summary of the transmissions observed is provided in Additional file 1: Table S3.


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

Yrigollen CM, Martorell L, Durbin-Johnson B, Naudo M, Genoves J, Murgia A, Polli R, Zhou L, Barbouth D, Rupchock A, Finucane B, Latham GJ, Hadd A, Berry-Kravis E, Tassone F - J Neurodev Disord (2014)

Predicted risk of a maternal premutation allele expanding to a full mutation during transmission. Risk calculated using total CGG length and separately for 0, 1, and 2 or 3 AGG interruptions (black, red, and green lines, respectively) in 710 transmissions. The difference in the predicted risk of expansion to a full mutation between alleles with 0 and 2 or 3 AGG interruptions is shown as a blue line.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4126815&req=5

Figure 1: Predicted risk of a maternal premutation allele expanding to a full mutation during transmission. Risk calculated using total CGG length and separately for 0, 1, and 2 or 3 AGG interruptions (black, red, and green lines, respectively) in 710 transmissions. The difference in the predicted risk of expansion to a full mutation between alleles with 0 and 2 or 3 AGG interruptions is shown as a blue line.
Mentions: The reported predicted risks of a premutation allele expanding to a full mutation allele during maternal transmission are based on the analyses of 710 transmission events from 525 premutation carrier mothers using CGG total length and number of AGG interruptions as variables (FigureĀ 1, Additional file 1: Table S2). A summary of the transmissions observed is provided in Additional file 1: Table S3.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, 2700 Stockton Blvd., Suite 2102, Sacramento, CA 95817, USA.

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.

No MeSH data available.


Related in: MedlinePlus