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. 1995 May;56(5):1147–1155.

The fragile X premutation in carriers and its effect on mutation size in offspring.

G S Fisch 1, K Snow 1, S N Thibodeau 1, M Chalifaux 1, J J Holden 1, D L Nelson 1, P N Howard-Peebles 1, A Maddalena 1
PMCID: PMC1801463  PMID: 7726171

Abstract

The pattern of inheritance in the fragile X (fra(X)) mutation follows a multistage intergenerational process in which the premutation evolves into the full mutation and the characteristic phenotype of the fra(X) syndrome after passing through oogenesis or a postzygotic event. Findings from our multicenter study confirm a strong direct relationship between fra(X) premutation size in the mother and probability of a full mutation in offspring with the mutation. Remarkably, the best-fitting equations are nonlinear asymptotic functions. The close approximation to both the logistic model and Gompertz suggests a process of accumulation of errors in DNA synthesis, as has been proposed previously. We also note that a larger-than-expected number of daughters of transmitting males have premutations that are smaller than their fathers', and that proportion is significantly higher than the proportion of daughters whose premutations are smaller than their mothers'. Intergenerational decreases in premutation size have been reported in other trinucleotide-repeat disorders and also appear to be parent-of-origin specific. Thus, while intergenerational expansion to the full mutation in fra(X) may manifest a postzygotic event, decreases in mutation size may occur during or prior to meiosis.

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Selected References

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  1. Abeliovich D., Lerer I., Pashut-Lavon I., Shmueli E., Raas-Rothschild A., Frydman M. Negative expansion of the myotonic dystrophy unstable sequence. Am J Hum Genet. 1993 Jun;52(6):1175–1181. [PMC free article] [PubMed] [Google Scholar]
  2. Amato A. A., Prior T. W., Barohn R. J., Snyder P., Papp A., Mendell J. R. Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology. 1993 Apr;43(4):791–794. doi: 10.1212/wnl.43.4.791. [DOI] [PubMed] [Google Scholar]
  3. Andrew S. E., Goldberg Y. P., Kremer B., Telenius H., Theilmann J., Adam S., Starr E., Squitieri F., Lin B., Kalchman M. A. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993 Aug;4(4):398–403. doi: 10.1038/ng0893-398. [DOI] [PubMed] [Google Scholar]
  4. Ashizawa T., Anvret M., Baiget M., Barceló J. M., Brunner H., Cobo A. M., Dallapiccola B., Fenwick R. G., Jr, Grandell U., Harley H. Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy. Am J Hum Genet. 1994 Mar;54(3):414–423. [PMC free article] [PubMed] [Google Scholar]
  5. Ashizawa T., Dubel J. R., Dunne P. W., Dunne C. J., Fu Y. H., Pizzuti A., Caskey C. T., Boerwinkle E., Perryman M. B., Epstein H. F. Anticipation in myotonic dystrophy. II. Complex relationships between clinical findings and structure of the GCT repeat. Neurology. 1992 Oct;42(10):1877–1883. doi: 10.1212/wnl.42.10.1877. [DOI] [PubMed] [Google Scholar]
  6. Ashizawa T., Dunne P. W., Ward P. A., Seltzer W. K., Richards C. S. Effects of the sex of myotonic dystrophy patients on the unstable triplet repeat in their affected offspring. Neurology. 1994 Jan;44(1):120–122. doi: 10.1212/wnl.44.1.120. [DOI] [PubMed] [Google Scholar]
  7. Brunner H. G., Brüggenwirth H. T., Nillesen W., Jansen G., Hamel B. C., Hoppe R. L., de Die C. E., Höweler C. J., van Oost B. A., Wieringa B. Influence of sex of the transmitting parent as well as of parental allele size on the CTG expansion in myotonic dystrophy (DM). Am J Hum Genet. 1993 Nov;53(5):1016–1023. [PMC free article] [PubMed] [Google Scholar]
  8. Brunner H. G., Jansen G., Nillesen W., Nelen M. R., de Die C. E., Höweler C. J., van Oost B. A., Wieringa B., Ropers H. H., Smeets H. J. Brief report: reverse mutation in myotonic dystrophy. N Engl J Med. 1993 Feb 18;328(7):476–480. doi: 10.1056/NEJM199302183280705. [DOI] [PubMed] [Google Scholar]
  9. Clayton-Smith J., Driscoll D. J., Waters M. F., Webb T., Andrews T., Malcolm S., Pembrey M. E., Nicholls R. D. Difference in methylation patterns within the D15S9 region of chromosome 15q11-13 in first cousins with Angelman syndrome and Prader-Willi syndrome. Am J Med Genet. 1993 Oct 1;47(5):683–686. doi: 10.1002/ajmg.1320470519. [DOI] [PubMed] [Google Scholar]
  10. Cobo A. M., Baiget M., López de Munain A., Poza J. J., Emparanza J. I., Johnson K. Sex-related difference in intergenerational expansion of myotonic dystrophy gene. Lancet. 1993 May 1;341(8853):1159–1160. doi: 10.1016/0140-6736(93)93186-5. [DOI] [PubMed] [Google Scholar]
  11. Eichler E. E., Holden J. J., Popovich B. W., Reiss A. L., Snow K., Thibodeau S. N., Richards C. S., Ward P. A., Nelson D. L. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet. 1994 Sep;8(1):88–94. doi: 10.1038/ng0994-88. [DOI] [PubMed] [Google Scholar]
  12. Fisch G. S., Nelson D. L., Snow K., Thibodeau S. N., Chalifoux M., Holden J. J. Reliability of diagnostic assessment of normal and premutation status in the fragile X syndrome using DNA testing. Am J Med Genet. 1994 Jul 15;51(4):339–345. doi: 10.1002/ajmg.1320510409. [DOI] [PubMed] [Google Scholar]
  13. Fu Y. H., Kuhl D. P., Pizzuti A., Pieretti M., Sutcliffe J. S., Richards S., Verkerk A. J., Holden J. J., Fenwick R. G., Jr, Warren S. T. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991 Dec 20;67(6):1047–1058. doi: 10.1016/0092-8674(91)90283-5. [DOI] [PubMed] [Google Scholar]
  14. Hall J. G. How imprinting is relevant to human disease. Dev Suppl. 1990:141–148. [PubMed] [Google Scholar]
  15. Hanzlik A. J., Osemlak-Hanzlik M. M., Hauser M. A., Kurnit D. M. A recombination-based assay demonstrates that the fragile X sequence is transcribed widely during development. Nat Genet. 1993 Jan;3(1):44–48. doi: 10.1038/ng0193-44. [DOI] [PubMed] [Google Scholar]
  16. Harley H. G., Brook J. D., Rundle S. A., Crow S., Reardon W., Buckler A. J., Harper P. S., Housman D. E., Shaw D. J. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature. 1992 Feb 6;355(6360):545–546. doi: 10.1038/355545a0. [DOI] [PubMed] [Google Scholar]
  17. Harley H. G., Rundle S. A., MacMillan J. C., Myring J., Brook J. D., Crow S., Reardon W., Fenton I., Shaw D. J., Harper P. S. Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy. Am J Hum Genet. 1993 Jun;52(6):1164–1174. [PMC free article] [PubMed] [Google Scholar]
  18. Heitz D., Devys D., Imbert G., Kretz C., Mandel J. L. Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation. J Med Genet. 1992 Nov;29(11):794–801. doi: 10.1136/jmg.29.11.794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Heitz D., Rousseau F., Devys D., Saccone S., Abderrahim H., Le Paslier D., Cohen D., Vincent A., Toniolo D., Della Valle G. Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island. Science. 1991 Mar 8;251(4998):1236–1239. doi: 10.1126/science.2006411. [DOI] [PubMed] [Google Scholar]
  20. Hunter A. G., Jacob P., O'Hoy K., MacDonald I., Mettler G., Tsilfidis C., Korneluk R. G. Decrease in the size of the myotonic dystrophy CTG repeat during transmission from parent to child: implications for genetic counselling and genetic anticipation. Am J Med Genet. 1993 Feb 1;45(3):401–407. doi: 10.1002/ajmg.1320450330. [DOI] [PubMed] [Google Scholar]
  21. Hunter A., Tsilfidis C., Mettler G., Jacob P., Mahadevan M., Surh L., Korneluk R. The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy. J Med Genet. 1992 Nov;29(11):774–779. doi: 10.1136/jmg.29.11.774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jansen G., Willems P., Coerwinkel M., Nillesen W., Smeets H., Vits L., Höweler C., Brunner H., Wieringa B. Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG)n repeat variation and selection against extreme expansion in sperm. Am J Hum Genet. 1994 Apr;54(4):575–585. [PMC free article] [PubMed] [Google Scholar]
  23. Kitsberg D., Selig S., Brandeis M., Simon I., Keshet I., Driscoll D. J., Nicholls R. D., Cedar H. Allele-specific replication timing of imprinted gene regions. Nature. 1993 Jul 29;364(6436):459–463. doi: 10.1038/364459a0. [DOI] [PubMed] [Google Scholar]
  24. Knight S. J., Flannery A. V., Hirst M. C., Campbell L., Christodoulou Z., Phelps S. R., Pointon J., Middleton-Price H. R., Barnicoat A., Pembrey M. E. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell. 1993 Jul 16;74(1):127–134. doi: 10.1016/0092-8674(93)90300-f. [DOI] [PubMed] [Google Scholar]
  25. Knight S. J., Voelckel M. A., Hirst M. C., Flannery A. V., Moncla A., Davies K. E. Triplet repeat expansion at the FRAXE locus and X-linked mild mental handicap. Am J Hum Genet. 1994 Jul;55(1):81–86. [PMC free article] [PubMed] [Google Scholar]
  26. Knoll J. H., Cheng S. D., Lalande M. Allele specificity of DNA replication timing in the Angelman/Prader-Willi syndrome imprinted chromosomal region. Nat Genet. 1994 Jan;6(1):41–46. doi: 10.1038/ng0194-41. [DOI] [PubMed] [Google Scholar]
  27. Koide R., Ikeuchi T., Onodera O., Tanaka H., Igarashi S., Endo K., Takahashi H., Kondo R., Ishikawa A., Hayashi T. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. 1994 Jan;6(1):9–13. doi: 10.1038/ng0194-9. [DOI] [PubMed] [Google Scholar]
  28. Kolehmainen K. Population genetics of fragile X: a multiple allele model with variable risk of CGG repeat expansion. Am J Med Genet. 1994 Jul 15;51(4):428–435. doi: 10.1002/ajmg.1320510425. [DOI] [PubMed] [Google Scholar]
  29. Krawczak M., Bockel B., Sandkuijl L., Thies U., Fenton I., Harper P. S. Covariate-dependent age-at-onset distributions for Huntington disease. Am J Hum Genet. 1991 Oct;49(4):735–745. [PMC free article] [PubMed] [Google Scholar]
  30. La Spada A. R., Wilson E. M., Lubahn D. B., Harding A. E., Fischbeck K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991 Jul 4;352(6330):77–79. doi: 10.1038/352077a0. [DOI] [PubMed] [Google Scholar]
  31. Laird C. D. Proposed mechanism of inheritance and expression of the human fragile-X syndrome of mental retardation. Genetics. 1987 Nov;117(3):587–599. doi: 10.1093/genetics/117.3.587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lavedan C., Hofmann-Radvanyi H., Rabes J. P., Roume J., Junien C. Different sex-dependent constraints in CTG length variation as explanation for congenital myotonic dystrophy. Lancet. 1993 Jan 23;341(8839):237–237. doi: 10.1016/0140-6736(93)90097-z. [DOI] [PubMed] [Google Scholar]
  33. Levinson G., Maddalena A., Palmer F. T., Harton G. L., Bick D. P., Howard-Peebles P. N., Black S. H., Schulman J. D. Improved sizing of fragile X CCG repeats by nested polymerase chain reaction. Am J Med Genet. 1994 Jul 15;51(4):527–534. doi: 10.1002/ajmg.1320510448. [DOI] [PubMed] [Google Scholar]
  34. Morton N. E., Macpherson J. N. Population genetics of the fragile-X syndrome: multiallelic model for the FMR1 locus. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4215–4217. doi: 10.1073/pnas.89.9.4215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mulley J. C., Staples A., Donnelly A., Gedeon A. K., Hecht B. K., Nicholson G. A., Haan E. A., Sutherland G. R. Explanation for exclusive maternal origin for congenital form of myotonic dystrophy. Lancet. 1993 Jan 23;341(8839):236–237. doi: 10.1016/0140-6736(93)90096-y. [DOI] [PubMed] [Google Scholar]
  36. Orr H. T., Chung M. Y., Banfi S., Kwiatkowski T. J., Jr, Servadio A., Beaudet A. L., McCall A. E., Duvick L. A., Ranum L. P., Zoghbi H. Y. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993 Jul;4(3):221–226. doi: 10.1038/ng0793-221. [DOI] [PubMed] [Google Scholar]
  37. Pembrey M. E., Winter R. M., Davies K. E. A premutation that generates a defect at crossing over explains the inheritance of fragile X mental retardation. Am J Med Genet. 1985 Aug;21(4):709–717. doi: 10.1002/ajmg.1320210413. [DOI] [PubMed] [Google Scholar]
  38. Reik W. Genomic imprinting: a possible mechanism for the parental origin effect in Huntington's chorea. J Med Genet. 1988 Dec;25(12):805–808. doi: 10.1136/jmg.25.12.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Reis A., Dittrich B., Greger V., Buiting K., Lalande M., Gillessen-Kaesbach G., Anvret M., Horsthemke B. Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes. Am J Hum Genet. 1994 May;54(5):741–747. [PMC free article] [PubMed] [Google Scholar]
  40. Reyniers E., Vits L., De Boulle K., Van Roy B., Van Velzen D., de Graaff E., Verkerk A. J., Jorens H. Z., Darby J. K., Oostra B. The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm. Nat Genet. 1993 Jun;4(2):143–146. doi: 10.1038/ng0693-143. [DOI] [PubMed] [Google Scholar]
  41. Richards R. I., Sutherland G. R. Heritable unstable DNA sequences. Nat Genet. 1992 Apr;1(1):7–9. doi: 10.1038/ng0492-7. [DOI] [PubMed] [Google Scholar]
  42. Ridley R. M., Frith C. D., Crow T. J., Conneally P. M. Anticipation in Huntington's disease is inherited through the male line but may originate in the female. J Med Genet. 1988 Sep;25(9):589–595. doi: 10.1136/jmg.25.9.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Riggs J. E. Aging and mortality: manifestations of increasing informational entropy of the genome? Mech Ageing Dev. 1993 Jan;66(3):249–256. doi: 10.1016/0047-6374(93)90012-g. [DOI] [PubMed] [Google Scholar]
  44. Rousseau F., Heitz D., Tarleton J., MacPherson J., Malmgren H., Dahl N., Barnicoat A., Mathew C., Mornet E., Tejada I. A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases. Am J Hum Genet. 1994 Aug;55(2):225–237. [PMC free article] [PubMed] [Google Scholar]
  45. Shelbourne P., Winqvist R., Kunert E., Davies J., Leisti J., Thiele H., Bachmann H., Buxton J., Williamson B., Johnson K. Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype. Hum Mol Genet. 1992 Oct;1(7):467–473. doi: 10.1093/hmg/1.7.467. [DOI] [PubMed] [Google Scholar]
  46. Sherman S. L., Morton N. E., Jacobs P. A., Turner G. The marker (X) syndrome: a cytogenetic and genetic analysis. Ann Hum Genet. 1984 Jan;48(Pt 1):21–37. doi: 10.1111/j.1469-1809.1984.tb00830.x. [DOI] [PubMed] [Google Scholar]
  47. Snell R. G., MacMillan J. C., Cheadle J. P., Fenton I., Lazarou L. P., Davies P., MacDonald M. E., Gusella J. F., Harper P. S., Shaw D. J. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet. 1993 Aug;4(4):393–397. doi: 10.1038/ng0893-393. [DOI] [PubMed] [Google Scholar]
  48. Snow K., Doud L. K., Hagerman R., Pergolizzi R. G., Erster S. H., Thibodeau S. N. Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population. Am J Hum Genet. 1993 Dec;53(6):1217–1228. [PMC free article] [PubMed] [Google Scholar]
  49. Strehler B. L., Freeman M. R. Randomness, redundancy and repair: roles and relevance to biological aging. Mech Ageing Dev. 1980 Sep-Oct;14(1-2):15–38. doi: 10.1016/0047-6374(80)90103-7. [DOI] [PubMed] [Google Scholar]
  50. Strehler B. L. Genetic instability as the primary cause of human aging. Exp Gerontol. 1986;21(4-5):283–319. doi: 10.1016/0531-5565(86)90038-0. [DOI] [PubMed] [Google Scholar]
  51. Verheij C., Bakker C. E., de Graaff E., Keulemans J., Willemsen R., Verkerk A. J., Galjaard H., Reuser A. J., Hoogeveen A. T., Oostra B. A. Characterization and localization of the FMR-1 gene product associated with fragile X syndrome. Nature. 1993 Jun 24;363(6431):722–724. doi: 10.1038/363722a0. [DOI] [PubMed] [Google Scholar]
  52. Verkerk A. J., Pieretti M., Sutcliffe J. S., Fu Y. H., Kuhl D. P., Pizzuti A., Reiner O., Richards S., Victoria M. F., Zhang F. P. 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 May 31;65(5):905–914. doi: 10.1016/0092-8674(91)90397-h. [DOI] [PubMed] [Google Scholar]
  53. Väisänen M. L., Kähkönen M., Leisti J. Diagnosis of fragile X syndrome by direct mutation analysis. Hum Genet. 1994 Feb;93(2):143–147. doi: 10.1007/BF00210599. [DOI] [PubMed] [Google Scholar]
  54. Webb T. P., Bundey S. E., Thake A. I., Todd J. Population incidence and segregation ratios in the Martin-Bell syndrome. Am J Med Genet. 1986 Jan-Feb;23(1-2):573–580. doi: 10.1002/ajmg.1320230151. [DOI] [PubMed] [Google Scholar]
  55. Willems P. J., Van Roy B., De Boulle K., Vits L., Reyniers E., Beck O., Dumon J. E., Verkerk A., Oostra B. Segregation of the fragile X mutation from an affected male to his normal daughter. Hum Mol Genet. 1992 Oct;1(7):511–515. doi: 10.1093/hmg/1.7.511. [DOI] [PubMed] [Google Scholar]
  56. Wosilait W. D., Luecke R. H., Young J. F. A mathematical analysis of human embryonic and fetal growth data. Growth Dev Aging. 1992 Winter;56(4):249–257. [PubMed] [Google Scholar]
  57. Wöhrle D., Hennig I., Vogel W., Steinbach P. Mitotic stability of fragile X mutations in differentiated cells indicates early post-conceptional trinucleotide repeat expansion. Nat Genet. 1993 Jun;4(2):140–142. doi: 10.1038/ng0693-140. [DOI] [PubMed] [Google Scholar]

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