Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1997 Jan;60(1):103–112.

Predisposition to the fragile X syndrome in Jews of Tunisian descent is due to the absence of AGG interruptions on a rare Mediterranean haplotype.

T C Falik-Zaccai 1, E Shachak 1, M Yalon 1, Z Lis 1, Z Borochowitz 1, J N Macpherson 1, D L Nelson 1, E E Eichler 1
PMCID: PMC1712540  PMID: 8981953

Abstract

We have studied the ethnic distribution of the fragile X syndrome in Israel and have found that 36/136 (26.5%) of apparently unrelated pedigrees were of Tunisian Jewish descent. The Tunisian Jews, however, constitute only 2%-3% of the general Israeli population, identifying the first ethnic group significantly (P < .001) predisposed to the development of this disease. Associated with this increase in disease prevalence, we have found an unusually high incidence of FMR1 CGG repeats devoid of AGG interruptions among the normal Tunisian Jewish population (30/150, or 20.0%). Furthermore, the proportion of these alleles beyond the FMR1 CGG repeat instability threshold (>35 repeats) (8/150, or 5.3%) was significantly greater (P < .04) than that proportion found among non-Tunisian Jewish controls in Israel (1/136). Haplotype analysis has indicated that these large uninterrupted CGG repeat alleles are present on a previously unreported (DXS548-FRAXAC1-FRAXAC2) haplotype that accounts for all observed cases of disease among Tunisian Jewish X chromosomes. The high prevalence of disease among Tunisian Jews, we suggest, is due to a founder effect of this rare haplotype, which is completely devoid of AGG interruptions in the Jewish population of Tunisia.

Full text

PDF
103

Selected References

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

  1. Aoi T., Takashima H., Takada T., Okada T. Fragile X chromosome in institutionalized male adults with mental retardation. Keio J Med. 1989 Mar;38(1):36–39. doi: 10.2302/kjm.38.36. [DOI] [PubMed] [Google Scholar]
  2. Arinami T., Asano M., Kobayashi K., Yanagi H., Hamaguchi H. Data on the CGG repeat at the fragile X site in the non-retarded Japanese population and family suggest the presence of a subgroup of normal alleles predisposing to mutate. Hum Genet. 1993 Nov;92(5):431–436. doi: 10.1007/BF00216445. [DOI] [PubMed] [Google Scholar]
  3. Arinami T., Kondo I., Nakajima S. Frequency of the fragile X syndrome in Japanese mentally retarded males. Hum Genet. 1986 Aug;73(4):309–312. doi: 10.1007/BF00279092. [DOI] [PubMed] [Google Scholar]
  4. Bundey S., Webb T. P., Thake A., Todd J. A community study of severe mental retardation in the West Midlands and the importance of the fragile X chromosome in its aetiology. J Med Genet. 1985 Aug;22(4):258–266. doi: 10.1136/jmg.22.4.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buyle S., Reyniers E., Vits L., De Boulle K., Handig I., Wuyts F. L., Deelen W., Halley D. J., Oostra B. A., Willems P. J. Founder effect in a Belgian-Dutch fragile X population. Hum Genet. 1993 Oct 1;92(3):269–272. doi: 10.1007/BF00244471. [DOI] [PubMed] [Google Scholar]
  6. Chakravarti A. Fragile X founder effect? Nat Genet. 1992 Jul;1(4):237–238. doi: 10.1038/ng0792-237. [DOI] [PubMed] [Google Scholar]
  7. Eichler E. E., Hammond H. A., Macpherson J. N., Ward P. A., Nelson D. L. Population survey of the human FMR1 CGG repeat substructure suggests biased polarity for the loss of AGG interruptions. Hum Mol Genet. 1995 Dec;4(12):2199–2208. doi: 10.1093/hmg/4.12.2199. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Eichler E. E., Macpherson J. N., Murray A., Jacobs P. A., Chakravarti A., Nelson D. L. Haplotype and interspersion analysis of the FMR1 CGG repeat identifies two different mutational pathways for the origin of the fragile X syndrome. Hum Mol Genet. 1996 Mar;5(3):319–330. doi: 10.1093/hmg/5.3.319. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Haataja R., Väisänen M. L., Li M., Ryynänen M., Leisti J. The fragile X syndrome in Finland: demonstration of a founder effect by analysis of microsatellite haplotypes. Hum Genet. 1994 Nov;94(5):479–483. doi: 10.1007/BF00211011. [DOI] [PubMed] [Google Scholar]
  12. Hirst M. C., Grewal P. K., Davies K. E. Precursor arrays for triplet repeat expansion at the fragile X locus. Hum Mol Genet. 1994 Sep;3(9):1553–1560. doi: 10.1093/hmg/3.9.1553. [DOI] [PubMed] [Google Scholar]
  13. Hirst M. C., Knight S. J., Christodoulou Z., Grewal P. K., Fryns J. P., Davies K. E. Origins of the fragile X syndrome mutation. J Med Genet. 1993 Aug;30(8):647–650. doi: 10.1136/jmg.30.8.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jacobs P. A., Bullman H., Macpherson J., Youings S., Rooney V., Watson A., Dennis N. R. Population studies of the fragile X: a molecular approach. J Med Genet. 1993 Jun;30(6):454–459. doi: 10.1136/jmg.30.6.454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jacobs P. A., Sherman S., Turner G., Webb T. The fragile (X) syndrome: the mutation problem. Am J Med Genet. 1986 Jan-Feb;23(1-2):611–617. doi: 10.1002/ajmg.1320230155. [DOI] [PubMed] [Google Scholar]
  16. Kunst C. B., Warren S. T. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell. 1994 Jun 17;77(6):853–861. doi: 10.1016/0092-8674(94)90134-1. [DOI] [PubMed] [Google Scholar]
  17. Li S. Y., Tsai C. C., Chou M. Y., Lin J. K. A cytogenetic study of mentally retarded school children in Taiwan with special reference to the fragile X chromosome. Hum Genet. 1988 Aug;79(4):292–296. doi: 10.1007/BF00282163. [DOI] [PubMed] [Google Scholar]
  18. Lucotte G., Smets P., Ruffié J. Y-chromosome-specific haplotype diversity in Ashkenazic and Sephardic Jews. Hum Biol. 1993 Oct;65(5):835–840. [PubMed] [Google Scholar]
  19. Macpherson J. N., Bullman H., Youings S. A., Jacobs P. A. Insert size and flanking haplotype in fragile X and normal populations: possible multiple origins for the fragile X mutation. Hum Mol Genet. 1994 Mar;3(3):399–405. doi: 10.1093/hmg/3.3.399. [DOI] [PubMed] [Google Scholar]
  20. Malmgren H., Gustavson K. H., Oudet C., Holmgren G., Pettersson U., Dahl N. Strong founder effect for the fragile X syndrome in Sweden. Eur J Hum Genet. 1994;2(2):103–109. doi: 10.1159/000472350. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Murray A., Youings S., Dennis N., Latsky L., Linehan P., McKechnie N., Macpherson J., Pound M., Jacobs P. Population screening at the FRAXA and FRAXE loci: molecular analyses of boys with learning difficulties and their mothers. Hum Mol Genet. 1996 Jun;5(6):727–735. doi: 10.1093/hmg/5.6.727. [DOI] [PubMed] [Google Scholar]
  23. Oudet C., Mornet E., Serre J. L., Thomas F., Lentes-Zengerling S., Kretz C., Deluchat C., Tejada I., Boué J., Boué A. Linkage disequilibrium between the fragile X mutation and two closely linked CA repeats suggests that fragile X chromosomes are derived from a small number of founder chromosomes. Am J Hum Genet. 1993 Feb;52(2):297–304. [PMC free article] [PubMed] [Google Scholar]
  24. Oudet C., von Koskull H., Nordström A. M., Peippo M., Mandel J. L. Striking founder effect for the fragile X syndrome in Finland. Eur J Hum Genet. 1993;1(3):181–189. doi: 10.1159/000472412. [DOI] [PubMed] [Google Scholar]
  25. RANQUE J., NICOLI R. M., GHERIB B., BATTAGLINI P. F. ETUDE S'ERO-ANTHROPOLOGIQUE DES JUIFS DE L' ILE DE DJERBA (TUNISIE) Bibl Haematol. 1964;19:210–212. [PubMed] [Google Scholar]
  26. Rhoads F. A. Fragile-X syndrome in Hawaii: a summary of clinical experience. Am J Med Genet. 1984 Jan;17(1):209–214. doi: 10.1002/ajmg.1320170113. [DOI] [PubMed] [Google Scholar]
  27. Richards R. I., Holman K., Friend K., Kremer E., Hillen D., Staples A., Brown W. T., Goonewardena P., Tarleton J., Schwartz C. Evidence of founder chromosomes in fragile X syndrome. Nat Genet. 1992 Jul;1(4):257–260. doi: 10.1038/ng0792-257. [DOI] [PubMed] [Google Scholar]
  28. Richards R. I., Kondo I., Holman K., Yamauchi M., Seki N., Kishi K., Staples A., Sutherland G. R., Hori T. Haplotype analysis at the FRAXA locus in the Japanese population. Am J Med Genet. 1994 Jul 15;51(4):412–416. doi: 10.1002/ajmg.1320510422. [DOI] [PubMed] [Google Scholar]
  29. Rousseau F., Rouillard P., Morel M. L., Khandjian E. W., Morgan K. Prevalence of carriers of premutation-size alleles of the FMRI gene--and implications for the population genetics of the fragile X syndrome. Am J Hum Genet. 1995 Nov;57(5):1006–1018. [PMC free article] [PubMed] [Google Scholar]
  30. Snow K., Tester D. J., Kruckeberg K. E., Schaid D. J., Thibodeau S. N. Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation. Hum Mol Genet. 1994 Sep;3(9):1543–1551. doi: 10.1093/hmg/3.9.1543. [DOI] [PubMed] [Google Scholar]
  31. Tikochinski Y., Ritte U., Gross S. R., Prager E. M., Wilson A. C. mtDNA polymorphism in two communities of Jews. Am J Hum Genet. 1991 Jan;48(1):129–136. [PMC free article] [PubMed] [Google Scholar]
  32. Turner G., Daniel A., Frost M. X-linked mental retardation, macro-orchidism, and the Xq27 fragile site. J Pediatr. 1980 May;96(5):837–841. doi: 10.1016/s0022-3476(80)80552-x. [DOI] [PubMed] [Google Scholar]
  33. Venter P. A., Op't Hof J., Coetzee D. J., Van der Walt C., Retief A. E. No marker (X) syndrome in autistic children. Hum Genet. 1984;67(1):107–107. doi: 10.1007/BF00270567. [DOI] [PubMed] [Google Scholar]
  34. Webb T. P., Bundey S., Thake A., Todd J. The frequency of the fragile X chromosome among schoolchildren in Coventry. J Med Genet. 1986 Oct;23(5):396–399. doi: 10.1136/jmg.23.5.396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zhong N., Dobkin C., Brown W. T. A complex mutable polymorphism located within the fragile X gene. Nat Genet. 1993 Nov;5(3):248–253. doi: 10.1038/ng1193-248. [DOI] [PubMed] [Google Scholar]
  36. Zhong N., Yang W., Dobkin C., Brown W. T. Fragile X gene instability: anchoring AGGs and linked microsatellites. Am J Hum Genet. 1995 Aug;57(2):351–361. [PMC free article] [PubMed] [Google Scholar]
  37. Zhong N., Ye L., Dobkin C., Brown W. T. Fragile X founder chromosome effects: linkage disequilibrium or microsatellite heterogeneity? Am J Med Genet. 1994 Jul 15;51(4):405–411. doi: 10.1002/ajmg.1320510421. [DOI] [PubMed] [Google Scholar]
  38. Zlotogora J., Chemke J. Medical genetics in Israel. Eur J Hum Genet. 1995;3(3):147–154. doi: 10.1159/000472290. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES