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Am J Hum Genet. Jan 1997; 60(1): 103–112.
PMCID: PMC1712540

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


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.

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  • 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. [PubMed]
  • 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. [PubMed]
  • 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. [PubMed]
  • Bundey S, Webb TP, 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. [PMC free article] [PubMed]
  • Buyle S, Reyniers E, Vits L, De Boulle K, Handig I, Wuyts FL, Deelen W, Halley DJ, Oostra BA, Willems PJ. Founder effect in a Belgian-Dutch fragile X population. Hum Genet. 1993 Oct 1;92(3):269–272. [PubMed]
  • Chakravarti A. Fragile X founder effect? Nat Genet. 1992 Jul;1(4):237–238. [PubMed]
  • 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. Hum Mol Genet. 1995 Dec;4(12):2199–2208. [PubMed]
  • Eichler EE, Holden JJ, Popovich BW, Reiss AL, Snow K, Thibodeau SN, Richards CS, Ward PA, Nelson DL. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet. 1994 Sep;8(1):88–94. [PubMed]
  • Eichler EE, Macpherson JN, Murray A, Jacobs PA, Chakravarti A, Nelson DL. 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. [PubMed]
  • Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG, Jr, Warren ST, et al. 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. [PubMed]
  • Haataja R, Väisänen ML, 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. [PubMed]
  • Hirst MC, Grewal PK, Davies KE. Precursor arrays for triplet repeat expansion at the fragile X locus. Hum Mol Genet. 1994 Sep;3(9):1553–1560. [PubMed]
  • Hirst MC, Knight SJ, Christodoulou Z, Grewal PK, Fryns JP, Davies KE. Origins of the fragile X syndrome mutation. J Med Genet. 1993 Aug;30(8):647–650. [PMC free article] [PubMed]
  • Jacobs PA, Bullman H, Macpherson J, Youings S, Rooney V, Watson A, Dennis NR. Population studies of the fragile X: a molecular approach. J Med Genet. 1993 Jun;30(6):454–459. [PMC free article] [PubMed]
  • Jacobs PA, 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. [PubMed]
  • Kunst CB, Warren ST. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell. 1994 Jun 17;77(6):853–861. [PubMed]
  • Li SY, Tsai CC, Chou MY, Lin JK. 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. [PubMed]
  • 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]
  • Macpherson JN, Bullman H, Youings SA, Jacobs PA. 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. [PubMed]
  • Malmgren H, Gustavson KH, 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. [PubMed]
  • Morton NE, Macpherson JN. 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. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Oudet C, Mornet E, Serre JL, Thomas F, Lentes-Zengerling S, Kretz C, Deluchat C, Tejada I, Boué J, Boué A, et al. 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]
  • Oudet C, von Koskull H, Nordström AM, Peippo M, Mandel JL. Striking founder effect for the fragile X syndrome in Finland. Eur J Hum Genet. 1993;1(3):181–189. [PubMed]
  • Rhoads FA. Fragile-X syndrome in Hawaii: a summary of clinical experience. Am J Med Genet. 1984 Jan;17(1):209–214. [PubMed]
  • Richards RI, Holman K, Friend K, Kremer E, Hillen D, Staples A, Brown WT, Goonewardena P, Tarleton J, Schwartz C, et al. Evidence of founder chromosomes in fragile X syndrome. Nat Genet. 1992 Jul;1(4):257–260. [PubMed]
  • Richards RI, Kondo I, Holman K, Yamauchi M, Seki N, Kishi K, Staples A, Sutherland GR, Hori T. Haplotype analysis at the FRAXA locus in the Japanese population. Am J Med Genet. 1994 Jul 15;51(4):412–416. [PubMed]
  • Rousseau F, Rouillard P, Morel ML, Khandjian EW, 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]
  • 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. Hum Mol Genet. 1994 Sep;3(9):1543–1551. [PubMed]
  • Tikochinski Y, Ritte U, Gross SR, Prager EM, Wilson AC. mtDNA polymorphism in two communities of Jews. Am J Hum Genet. 1991 Jan;48(1):129–136. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Venter PA, Op't Hof J, Coetzee DJ, Van der Walt C, Retief AE. No marker (X) syndrome in autistic children. Hum Genet. 1984;67(1):107–107. [PubMed]
  • Webb TP, 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. [PMC free article] [PubMed]
  • Zhong N, Dobkin C, Brown WT. A complex mutable polymorphism located within the fragile X gene. Nat Genet. 1993 Nov;5(3):248–253. [PubMed]
  • Zhong N, Yang W, Dobkin C, Brown WT. Fragile X gene instability: anchoring AGGs and linked microsatellites. Am J Hum Genet. 1995 Aug;57(2):351–361. [PMC free article] [PubMed]
  • Zhong N, Ye L, Dobkin C, Brown WT. Fragile X founder chromosome effects: linkage disequilibrium or microsatellite heterogeneity? Am J Med Genet. 1994 Jul 15;51(4):405–411. [PubMed]
  • Zlotogora J, Chemke J. Medical genetics in Israel. Eur J Hum Genet. 1995;3(3):147–154. [PubMed]

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