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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

Magnitude of instability of unstable alleles that do not expand to a full mutation. Instability, as measured by the number of CGG repeats an allele increases during transmission, increases with an increase in CGG repeat size.
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Figure 4: Magnitude of instability of unstable alleles that do not expand to a full mutation. Instability, as measured by the number of CGG repeats an allele increases during transmission, increases with an increase in CGG repeat size.

Mentions: Table 2 shows the results of the mixed effects linear regression analysis of magnitude of expansion. The magnitude of expansion increased significantly with increasing total CGG length (P <0.001), with a predicted increase of 1.3 repeats in magnitude of expansion for each additional parental CGG repeat (Figure 4). The magnitude of expansion decreased significantly with increasing numbers of AGG interruptions, with an estimated difference of 9.8 fewer repeats in expansion with 1 parental AGG interruption versus 0 interruptions (P = 0.031), and an estimated difference of 15.2 fewer repeats in expansion with 2 or 3 AGG interruptions versus 0 interruptions (P = 0.001). Results are similar to those for both mothers and fathers.


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)

Magnitude of instability of unstable alleles that do not expand to a full mutation. Instability, as measured by the number of CGG repeats an allele increases during transmission, increases with an increase in CGG repeat size.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Magnitude of instability of unstable alleles that do not expand to a full mutation. Instability, as measured by the number of CGG repeats an allele increases during transmission, increases with an increase in CGG repeat size.
Mentions: Table 2 shows the results of the mixed effects linear regression analysis of magnitude of expansion. The magnitude of expansion increased significantly with increasing total CGG length (P <0.001), with a predicted increase of 1.3 repeats in magnitude of expansion for each additional parental CGG repeat (Figure 4). The magnitude of expansion decreased significantly with increasing numbers of AGG interruptions, with an estimated difference of 9.8 fewer repeats in expansion with 1 parental AGG interruption versus 0 interruptions (P = 0.031), and an estimated difference of 15.2 fewer repeats in expansion with 2 or 3 AGG interruptions versus 0 interruptions (P = 0.001). Results are similar to those for both mothers and fathers.

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