The online version of this article (doi:10.1186/1866-1955-6-24) contains supplementary material, which is available to authorized users.
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.
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.
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.
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.
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.
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.
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)11689_2013_80_MOESM1_ESM.docx
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)11689_2013_80_MOESM2_ESM.tiff
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)11689_2013_80_MOESM3_ESM.tiff
Authors’ original file for figure 111689_2013_80_MOESM4_ESM.tiff
Authors’ original file for figure 211689_2013_80_MOESM5_ESM.tiff
Authors’ original file for figure 311689_2013_80_MOESM6_ESM.tiff
Authors’ original file for figure 411689_2013_80_MOESM7_ESM.tiff
Authors’ original file for figure 511689_2013_80_MOESM8_ESM.tiff
Authors’ original file for figure 611689_2013_80_MOESM9_ESM.tiff
Authors’ original file for figure 711689_2013_80_MOESM10_ESM.tiff
Authors’ original file for figure 811689_2013_80_MOESM11_ESM.tiff
Authors’ original file for figure 911689_2013_80_MOESM12_ESM.tiff
Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG, Warren ST, Oostra BA, Nelson DL, Caskey CT: Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991, 67: 1047-1058. PubMedCrossRef
Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, Eussen BE, van Ommen GJB, Blonden LAJ, Riggins GJ, Chastain JL, Kunst CB, Galjaard H, Caskey CT, Nelson DL, Oostra BA, Warren ST: Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991, 65: 905-914. PubMedCrossRef
Eichler EE, Hammond HA, Macpherson JN, Ward PA, Nelson DL: Population survey of the human FMR1 CGG repeat substructure suggests biased polarity for the loss of AGG interruptions. Human Mole Genet. 1995, 4: 2199-2208. CrossRef
Snow K, Tester DJ, Kruckeberg KE, Schaid DJ, Thibodeau SN: Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation. Human Mole Genet. 1994, 3: 1543-1551. CrossRef
Zhong N, Yang W, Dobkin C, Brown WT: Fragile X gene instability: anchoring AGGs and linked microsatellites. Am J Human Genet. 1995, 57: 351-361.
Nolin SL, Sah S, Glicksman A, Sherman SL, Allen E, Berry-Kravis E, Tassone F, Yrigollen C, Cronister A, Jodah M, Ersalesi N, Dobkin C, Brown WT, Shroff R, Latham GJ, Hadd AG: Fragile X AGG analysis provides new risk predictions for 45–69 repeat alleles. Am J Med Genet A. 2013, 161: 771-778. CrossRef
Peprah E, He W, Allen E, Oliver T, Boyne A, Sherman SL: Examination of FMR1 transcript and protein levels among 74 premutation carriers. J Human Genet. 2010, 55: 66-68. CrossRef
Chen L, Hadd A, Sah S, Filipovic-Sadic S, Krosting J, Sekinger E, Pan R, Hagerman PJ, Stenzel TT, Tassone F, Latham GJ: An information-rich CGG repeat primed PCR that detects the full range of fragile X expanded alleles and minimizes the need for southern blot analysis. J Mol Diagn. 2010, 12: 589-600. PubMedPubMedCentralCrossRef
Lokanga RA, Zhao XN, Usdin K: The mismatch repair protein MSH2 is rate limiting for repeat expansion in a fragile X premutation mouse model. Human Mut. 2013, 35: 129-136. CrossRef
Team RC: A language and environment for statistical computing. 2013, Vienna, Austria: R Foundation for Statistical Computing, Available: http://www.R-project.org/
Mornet E, Jokic M, Bogyo A, Tejada I, Deluchat C, Boue J, Boue A: Affected sibs with fragile X syndrome exhibit an age-dependent decrease in the size of the fragile X full mutation. Clin Gen. 1993, 43: 157-159. CrossRef
Ashley-Koch AE, Robinson H, Glicksman AE, Nolin SL, Schwartz CE, Brown WT, Turner G, Sherman SL: Examination of factors associated with instability of the FMR1 CGG repeat. Am J Human Genet. 1998, 63: 776-785. CrossRef
Nolin SL, Glicksman A, Ding X, Ersalesi N, Brown WT, Sherman SL, Dobkin C: Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenatal Diagn. 2011, 31: 925-931. CrossRef
- AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission
Carolyn M Yrigollen
Gary J Latham
- BioMed Central
Neu im Fachgebiet Psychiatrie
Meistgelesene Bücher aus dem Fachgebiet