Limits...
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

Maternal age, total length, and number of AGG predict risk of full mutation expansion. The diagram shows the risk of expansion to a full mutation in a 20-, 30-, and 40-year-old premutation carrier mother predicted for 0 (black), 1 (red), and 2 or 3 (green) AGG interruptions and total length of CGG repeats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Maternal age, total length, and number of AGG predict risk of full mutation expansion. The diagram shows the risk of expansion to a full mutation in a 20-, 30-, and 40-year-old premutation carrier mother predicted for 0 (black), 1 (red), and 2 or 3 (green) AGG interruptions and total length of CGG repeats.

Mentions: The AIC score for total length and number of AGG interruptions using 710 transmissions was found to be 252.8 and decreased to 241.6 when maternal age was included. Total CGG length, pure CGG stretch, number of AGG interruptions, and maternal age were all tested within 1, 2, or 3 variable models and given an AIC score that measures the fit of the model to the observed data and the number of variables within the model. The scores ranged from 235.6 (a model with pure stretch, AGG number, and maternal age as variables) to 444.8 (a model using only maternal age). The AIC for length of the pure stretch and number of AGG interruptions was 245.7 and decreased to 235.6 when maternal age was included. A comparison of the two primary models (one that includes total length, number of AGG interruptions, and maternal age and another that considers pure stretch, number of AGG interruptions and maternal age) indicated that the model that included total length rather than pure stretch produced risk estimates that were more consistent with our findings regarding the effect each variable had on risk. The model with the lowest AIC (pure stretch, number of AGG interruptions, and maternal age) predicted the highest risk of expansion to a full mutation to occur in alleles with 1 AGG interruption, a deviation from expected outcomes. This deviation is likely the result of insufficient observations of 2 or 3 AGG interruption transmissions. The predictive risk model calculated using total CGG length, number of AGG interruptions, and maternal age is illustrated in Figure 3. Table 1 summarizes the predicted risks of expansion to a full mutation of a premutation carrier female at 20, 30, and 40 years of age at the time of child birth. Noticeably, a differentiated risk of 94% is observed between a 20-year-old mother with 2 AGG interruptions (lower risk group) and a 40-year-old mother with 0 AGG interruptions (higher risk group) for an allele with a total length of 75 CGG repeats. Maternal age was compared for transmissions that resulted in a premutation to those that resulted in a full mutation, to test for ascertainment bias. No significant age difference was found (P = 0.975), with the mean age in both groups being 29.7 years.


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)

Maternal age, total length, and number of AGG predict risk of full mutation expansion. The diagram shows the risk of expansion to a full mutation in a 20-, 30-, and 40-year-old premutation carrier mother predicted for 0 (black), 1 (red), and 2 or 3 (green) AGG interruptions and total length of CGG repeats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Maternal age, total length, and number of AGG predict risk of full mutation expansion. The diagram shows the risk of expansion to a full mutation in a 20-, 30-, and 40-year-old premutation carrier mother predicted for 0 (black), 1 (red), and 2 or 3 (green) AGG interruptions and total length of CGG repeats.
Mentions: The AIC score for total length and number of AGG interruptions using 710 transmissions was found to be 252.8 and decreased to 241.6 when maternal age was included. Total CGG length, pure CGG stretch, number of AGG interruptions, and maternal age were all tested within 1, 2, or 3 variable models and given an AIC score that measures the fit of the model to the observed data and the number of variables within the model. The scores ranged from 235.6 (a model with pure stretch, AGG number, and maternal age as variables) to 444.8 (a model using only maternal age). The AIC for length of the pure stretch and number of AGG interruptions was 245.7 and decreased to 235.6 when maternal age was included. A comparison of the two primary models (one that includes total length, number of AGG interruptions, and maternal age and another that considers pure stretch, number of AGG interruptions and maternal age) indicated that the model that included total length rather than pure stretch produced risk estimates that were more consistent with our findings regarding the effect each variable had on risk. The model with the lowest AIC (pure stretch, number of AGG interruptions, and maternal age) predicted the highest risk of expansion to a full mutation to occur in alleles with 1 AGG interruption, a deviation from expected outcomes. This deviation is likely the result of insufficient observations of 2 or 3 AGG interruption transmissions. The predictive risk model calculated using total CGG length, number of AGG interruptions, and maternal age is illustrated in Figure 3. Table 1 summarizes the predicted risks of expansion to a full mutation of a premutation carrier female at 20, 30, and 40 years of age at the time of child birth. Noticeably, a differentiated risk of 94% is observed between a 20-year-old mother with 2 AGG interruptions (lower risk group) and a 40-year-old mother with 0 AGG interruptions (higher risk group) for an allele with a total length of 75 CGG repeats. Maternal age was compared for transmissions that resulted in a premutation to those that resulted in a full mutation, to test for ascertainment bias. No significant age difference was found (P = 0.975), with the mean age in both groups being 29.7 years.

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