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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

Distribution of premutation allele total length. A histogram of the number of transmissions observed for each total CGG repeat length, grouped by 0 (black), 1 (red), and 2 or 3 (green) AGG interruptions. Transmissions that resulted in a premutation are partially shaded, and transmissions that expanded to a full mutation are shown as solid bars.
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Figure 2: Distribution of premutation allele total length. A histogram of the number of transmissions observed for each total CGG repeat length, grouped by 0 (black), 1 (red), and 2 or 3 (green) AGG interruptions. Transmissions that resulted in a premutation are partially shaded, and transmissions that expanded to a full mutation are shown as solid bars.

Mentions: A model of the predicted risk of expansion to a full mutation using total CGG repeat length and number of AGG interruptions as risk factors showed no significant difference in any of the three sites analyzed separately compared to the combined data (135 UC Davis, 86 Rush University, and 105 Hospital Sant Joan de Dèu). University of Padova was not analyzed separately due to the smaller sample size, but was included in the analyses that combined sites together. In each of the groups the frequency of expansion to a full mutation increased with the total length of the CGG repeat. An overall lower frequency was observed in alleles between approximately 60 and 80 total CGG repeats when the allele contained 1 AGG interruption compared to 0, and with 2 or 3 AGG interruptions when compared to 1 or 0. A model of the predicted risk of expansion to a full mutation using total CGG repeat length and number of AGG interruptions as risk factors showed no significant difference in any of the three sites analyzed separately compared to the combined data. These findings also indicate that expansion risk is not related to ethnicity as the ethnic composition is different in the three sites being as follows: UC Davis: 64% White, 7% Black, 38% Hispanic; Rush University: 22% White, 38% Black, 29% Hispanic; Hospital Sant Joan de Dèu: approximately 100% Hispanic.The transmission results across sites were combined and analyzed. The majority of transmissions were between 70 and 100 repeats. The distribution of maternal total CGG length for the 710 transmissions is shown in Figure 2.


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)

Distribution of premutation allele total length. A histogram of the number of transmissions observed for each total CGG repeat length, grouped by 0 (black), 1 (red), and 2 or 3 (green) AGG interruptions. Transmissions that resulted in a premutation are partially shaded, and transmissions that expanded to a full mutation are shown as solid bars.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Distribution of premutation allele total length. A histogram of the number of transmissions observed for each total CGG repeat length, grouped by 0 (black), 1 (red), and 2 or 3 (green) AGG interruptions. Transmissions that resulted in a premutation are partially shaded, and transmissions that expanded to a full mutation are shown as solid bars.
Mentions: A model of the predicted risk of expansion to a full mutation using total CGG repeat length and number of AGG interruptions as risk factors showed no significant difference in any of the three sites analyzed separately compared to the combined data (135 UC Davis, 86 Rush University, and 105 Hospital Sant Joan de Dèu). University of Padova was not analyzed separately due to the smaller sample size, but was included in the analyses that combined sites together. In each of the groups the frequency of expansion to a full mutation increased with the total length of the CGG repeat. An overall lower frequency was observed in alleles between approximately 60 and 80 total CGG repeats when the allele contained 1 AGG interruption compared to 0, and with 2 or 3 AGG interruptions when compared to 1 or 0. A model of the predicted risk of expansion to a full mutation using total CGG repeat length and number of AGG interruptions as risk factors showed no significant difference in any of the three sites analyzed separately compared to the combined data. These findings also indicate that expansion risk is not related to ethnicity as the ethnic composition is different in the three sites being as follows: UC Davis: 64% White, 7% Black, 38% Hispanic; Rush University: 22% White, 38% Black, 29% Hispanic; Hospital Sant Joan de Dèu: approximately 100% Hispanic.The transmission results across sites were combined and analyzed. The majority of transmissions were between 70 and 100 repeats. The distribution of maternal total CGG length for the 710 transmissions is shown in Figure 2.

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