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. 1992 Nov;29(11):794–801. doi: 10.1136/jmg.29.11.794

Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation.

D Heitz 1, D Devys 1, G Imbert 1, C Kretz 1, J L Mandel 1
PMCID: PMC1016175  PMID: 1453430

Abstract

The fragile X mental retardation syndrome is caused by unstable expansion of a CGG repeat. Two main types of mutation have been categorised. Clinical expression is associated with the presence of the full mutation, while subjects who carry only a premutation do not have mental retardation. Premutations have a high risk of transition to full mutation when transmitted by a female. We have used direct detection of the mutations to characterise large families who illustrate the wide variation in penetrance which has been observed in different sibships (a feature often called the Sherman paradox). A family originally found to show tight genetic linkage between the factor 9 gene and the fragile X locus was reanalysed, confirming the original genotype assignments and the observed linkage. The size of premutations was measured by Southern blotting and by using a PCR based test in 102 carrier mothers and this was correlated with the type of mutation found in their offspring. The risk of transition to full mutation was found to be very low for premutations with a size increase (delta) of about 100 bp, increasing up to 100% when the size of premutation was larger than about 200 bp, even after taking into account (at least partially) ascertainment bias. These results confirm and extend those reported by Fu et al (1991) and Yu et al (1992) and explain the Sherman paradox.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arveiler B., Oberlé I., Vincent A., Hofker M. H., Pearson P. L., Mandel J. L. Genetic mapping of the Xq27-q28 region: new RFLP markers useful for diagnostic applications in fragile-X and hemophilia-B families. Am J Hum Genet. 1988 Feb;42(2):380–389. [PMC free article] [PubMed] [Google Scholar]
  2. Bell M. V., Hirst M. C., Nakahori Y., MacKinnon R. N., Roche A., Flint T. J., Jacobs P. A., Tommerup N., Tranebjaerg L., Froster-Iskenius U. Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome. Cell. 1991 Feb 22;64(4):861–866. doi: 10.1016/0092-8674(91)90514-y. [DOI] [PubMed] [Google Scholar]
  3. Brook J. D., McCurrach M. E., Harley H. G., Buckler A. J., Church D., Aburatani H., Hunter K., Stanton V. P., Thirion J. P., Hudson T. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 1992 Feb 21;68(4):799–808. doi: 10.1016/0092-8674(92)90154-5. [DOI] [PubMed] [Google Scholar]
  4. Brown W. T., Gross A., Chan C., Jenkins E. C., Mandel J. L., Oberlé I., Arveiler B., Novelli G., Thibodeau S., Hagerman R. Multilocus analysis of the fragile X syndrome. Hum Genet. 1988 Mar;78(3):201–205. doi: 10.1007/BF00291662. [DOI] [PubMed] [Google Scholar]
  5. Camerino G., Mattei M. G., Mattei J. F., Jaye M., Mandel J. L. Close linkage of fragile X-mental retardation syndrome to haemophilia B and transmission through a normal male. Nature. 1983 Dec 15;306(5944):701–704. doi: 10.1038/306701a0. [DOI] [PubMed] [Google Scholar]
  6. Devys D., Biancalana V., Rousseau F., Boué J., Mandel J. L., Oberlé I. Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. 1992 Apr 15-May 1Am J Med Genet. 43(1-2):208–216. doi: 10.1002/ajmg.1320430134. [DOI] [PubMed] [Google Scholar]
  7. Frank D., Keshet I., Shani M., Levine A., Razin A., Cedar H. Demethylation of CpG islands in embryonic cells. Nature. 1991 May 16;351(6323):239–241. doi: 10.1038/351239a0. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Fu Y. H., Pizzuti A., Fenwick R. G., Jr, King J., Rajnarayan S., Dunne P. W., Dubel J., Nasser G. A., Ashizawa T., de Jong P. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science. 1992 Mar 6;255(5049):1256–1258. doi: 10.1126/science.1546326. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Kremer E. J., Pritchard M., Lynch M., Yu S., Holman K., Baker E., Warren S. T., Schlessinger D., Sutherland G. R., Richards R. I. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science. 1991 Jun 21;252(5013):1711–1714. doi: 10.1126/science.1675488. [DOI] [PubMed] [Google Scholar]
  12. Laird C. D., Lamb M. M., Thorne J. L. Two progenitor cells for human oogonia inferred from pedigree data and the X-inactivation imprinting model of the fragile-X syndrome. Am J Hum Genet. 1990 Apr;46(4):696–719. [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Macpherson J., Harvey J., Curtis G., Webb T., Heitz D., Rousseau F., Jacobs P. A reinvestigation of thirty three fragile(X) families using probe StB12.3. Am J Med Genet. 1992 Jul 15;43(5):905–912. doi: 10.1002/ajmg.1320430535. [DOI] [PubMed] [Google Scholar]
  15. Mahadevan M., Tsilfidis C., Sabourin L., Shutler G., Amemiya C., Jansen G., Neville C., Narang M., Barceló J., O'Hoy K. Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science. 1992 Mar 6;255(5049):1253–1255. doi: 10.1126/science.1546325. [DOI] [PubMed] [Google Scholar]
  16. McConlogue L., Brow M. A., Innis M. A. Structure-independent DNA amplification by PCR using 7-deaza-2'-deoxyguanosine. Nucleic Acids Res. 1988 Oct 25;16(20):9869–9869. doi: 10.1093/nar/16.20.9869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Migeon B. R., Holland M. M., Driscoll D. J., Robinson J. C. Programmed demethylation in CpG islands during human fetal development. Somat Cell Mol Genet. 1991 Mar;17(2):159–168. doi: 10.1007/BF01232973. [DOI] [PubMed] [Google Scholar]
  18. Migeon B. R. Insights into X chromosome inactivation from studies of species variation, DNA methylation and replication, and vice versa. Genet Res. 1990 Oct-Dec;56(2-3):91–98. doi: 10.1017/s0016672300035151. [DOI] [PubMed] [Google Scholar]
  19. Migeon B. R., Wolf S. F., Axelman J., Kaslow D. C., Schmidt M. Incomplete X chromosome dosage compensation in chorionic villi of human placenta. Proc Natl Acad Sci U S A. 1985 May;82(10):3390–3394. doi: 10.1073/pnas.82.10.3390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pergolizzi R. G., Erster S. H., Goonewardena P., Brown W. T. Detection of full fragile X mutation. Lancet. 1992 Feb 1;339(8788):271–272. doi: 10.1016/0140-6736(92)91334-5. [DOI] [PubMed] [Google Scholar]
  21. Pieretti M., Zhang F. P., Fu Y. H., Warren S. T., Oostra B. A., Caskey C. T., Nelson D. L. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991 Aug 23;66(4):817–822. doi: 10.1016/0092-8674(91)90125-i. [DOI] [PubMed] [Google Scholar]
  22. Richards R. I., Holman K., Kozman H., Kremer E., Lynch M., Pritchard M., Yu S., Mulley J., Sutherland G. R. Fragile X syndrome: genetic localisation by linkage mapping of two microsatellite repeats FRAXAC1 and FRAXAC2 which immediately flank the fragile site. J Med Genet. 1991 Dec;28(12):818–823. doi: 10.1136/jmg.28.12.818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rousseau F., Heitz D., Biancalana V., Blumenfeld S., Kretz C., Boué J., Tommerup N., Van Der Hagen C., DeLozier-Blanchet C., Croquette M. F. Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med. 1991 Dec 12;325(24):1673–1681. doi: 10.1056/NEJM199112123252401. [DOI] [PubMed] [Google Scholar]
  24. Rousseau F., Heitz D., Biancalana V., Oberlé I., Mandel J. L. On some technical aspects of direct DNA diagnosis of the fragile X syndrome. 1992 Apr 15-May 1Am J Med Genet. 43(1-2):197–207. doi: 10.1002/ajmg.1320430133. [DOI] [PubMed] [Google Scholar]
  25. Rousseau F., Heitz D., Oberlé I., Mandel J. L. Selection in blood cells from female carriers of the fragile X syndrome: inverse correlation between age and proportion of active X chromosomes carrying the full mutation. J Med Genet. 1991 Dec;28(12):830–836. doi: 10.1136/jmg.28.12.830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sherman S. L., Jacobs P. A., Morton N. E., Froster-Iskenius U., Howard-Peebles P. N., Nielsen K. B., Partington M. W., Sutherland G. R., Turner G., Watson M. Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Hum Genet. 1985;69(4):289–299. doi: 10.1007/BF00291644. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Vincent A., Heitz D., Petit C., Kretz C., Oberlé I., Mandel J. L. Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis. Nature. 1991 Feb 14;349(6310):624–626. doi: 10.1038/349624a0. [DOI] [PubMed] [Google Scholar]
  29. Weber J. L. Informativeness of human (dC-dA)n.(dG-dT)n polymorphisms. Genomics. 1990 Aug;7(4):524–530. doi: 10.1016/0888-7543(90)90195-z. [DOI] [PubMed] [Google Scholar]
  30. Yu S., Mulley J., Loesch D., Turner G., Donnelly A., Gedeon A., Hillen D., Kremer E., Lynch M., Pritchard M. Fragile-X syndrome: unique genetics of the heritable unstable element. Am J Hum Genet. 1992 May;50(5):968–980. [PMC free article] [PubMed] [Google Scholar]

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