Abstract
For many years, the high prevalence of the fragile X syndrome was thought to be caused by a high mutation frequency. The recent isolation of the FMR1 gene and identification of the most prevalent mutation enable a more precise study of the fragile X mutation. As the vast majority of fragile X patients show amplification of an unstable trinucleotide repeat, DNA studies can now trace back the origin of the fragile X mutation. To date, de novo mutations leading to amplification of the CGG repeat have not yet been detected. Recently, linkage disequilibrium was found in the Australian and US populations between the fragile X mutation and adjacent polymorphic markers, suggesting a founder effect of the fragile X mutation. We present here a molecular study of Belgian and Dutch fragile X families. No de novo mutations could be found in 54 of these families. Moreover, we found significant (P < 0.0001) linkage disequilibrium in 68 unrelated fragile X patients between the fragile X mutation and an adjacent polymorphic microsatellite at DXS548. This suggests that a founder effect of the fragile X mutation also exists in the Belgian and Dutch populations. Both the absence of new mutations and the presence of linkage disequilibrium suggest that a few ancestral mutations are responsible for most of the patients with fragile X syndrome.
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Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T, Sohn R, Zemelman B, Snell RG, Rundle SA, Crow S, Davies J, Shelbourne P, Buxton J, Jones C, Juvonen V, Johnson K, Harper PS, Shaw DJ, Housman DE (1992) 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 68:799–808
Brown WT (1990) The fragile X: progress toward solving the puzzle. Am J Hum Genet 47:175–180
Brunner HG, Jansen G, Nillesen W, Nelen MR, Die CEM de, Höweler CJ, Oost BA van, Wieringa B, Ropers H-H, Smeets HJM (1992) Reverse mutation in myotonic dystrophy. N Engl J Med (in press)
Cavalli-Sforza LL, Piazza A (1993) Human genomic diversity in Europe: a summary of recent research and prospects for the future. Eur J Hum Genet 1:3–18
Chakravarti A (1992) Fragile X founder effect? Nature Genet 1:237–238
Froster-Iskenius U, Schulze A, Schwinger E (1984) Transmission of the marker X syndrome trait by unaffected males: conclusions from studies of large families. Hum Genet 67:419–427
Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG Jr, Warren ST, Oostra BA, Nelson DL, Caskey CT (1991) Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67:1047–1058
Gustavson KH, Blomquist H, Holmgren G (1986) Prevalence of fragile X syndrome in mentally retarded children in a Swedish county. Am J Med Genet 23:581–588
Haldane JBS (1935) J Genet 31:317–326
Harley HG, Brook JD, Floyd J, Rundle SA, Crow S, Walsh KV, Thibault MC, Harper PS, Shaw DJ (1991) Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker. Am J Hum Genet 49:68–75
Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI (1991) Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252:1711–1714
Morton NE, MacPherson JN (1992) Population genetics of the fragile-X syndrome: multiallelic model for the FMR1 locus. Proc Natl Acad Sci USA 89:4215–4217
Pieretti M, Zhang F, Fu Y-H, Warren ST, Oostra BA, Caskey CT, Nelson DL (1991) Absence of expression of the FMR-1 gene in fragile-X syndrome. Cell 66:817–822
Richards RI, Holman K, Friend K, Kremer E, Hillen D, Staples A, Brown WT, Goonewardena P, Tarleton J, Schwartz C, Sutherland GR (1992) Evidence of founder chromosomes in fragile X syndrome. Nature Genet 1:257–260
Riggins GJ, Sherman SL, Oostra BA, Sutcliffe JS, Feitell D, Nelson DL, Oost BA van, Smits AP, Ramos FJ, Pfendner E, Kuhl D, Caskey CT, Warren ST (1992) Characterization of a highly polymorphic dinucleotide repeat 150 kb proximal to the fragile X site. Am J Med Genet 43:237–243
Rousseau F, Heitz D, Biancalana V, Blumenfeld S, Kretz C, Boué J, Tommerup N, Van Der Hagen C, DeLozier-Blanchet C, Croquette M-F, Gilgenkrantz S, Jalbert P, Voelckel M-A, Oberlé I, Mandel J-L (1991) Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med 325:1673–1681
Shelbourne P, Winqvist R, Kunert E, Davies J, Leisti J, Thiele H, Bachmann H, Buxton J, Williamson B, Johnson K (1992) Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype. Hum Mol Genet 1: 467–473
Sherman SL, Morton NE, Jacobs PA, Turner G (1984) The marker (X) syndrome: a cytogenetic and genetic analysis. Ann Hum Genet 48:21–37
Sherman SL, Jacobs PA, Morton NE, Froster-Iskenius U, HowardPeebles PN, Nielsen KB, Partington MW, Sutherland GR, Turner G, Watson M (1985) Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Hum Genet 69:289–299
Sherman SL, Turner G, Robinson H, Laing S (1988) Investigation of the segregation of the fragile X mutation in daughters of obligate carrier women. Am J Med Genet 30:633–639
Smits A, Smeets D, Hamel B, Dreesen J, Oost B van (1992) High prevalence of the fra(X) syndrome cannot be explained by a high mutation rate. Am J Med Genet 43:345–352
Smits APT, Dreesen JCFM, Post JG, Smeets DFCM, Die-Smulders C, Spaans-van der Bijl T, Govaerts LCP, Warren ST, Oostra BA, Oost BA van (1993) The fragile X syndrome: no evidence for any recent mutations. J Med Genet 30:101–103
Van Roy BC, De Smedt MC, Raes RA, Dumon JE, Leroy JG (1983) Fragile X trait in a large kindred: transmission also through normal males. J Med Genet 20:286–289
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 (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914
Willems PJ, Van Roy B, De Boulle K, Vits L, Reyniers E, Beck O, Dumon JE, Verkerk A, Oostra B (1992) Segregation of the fragile X mutation from an affected male to his normal daughter. Hum Mol Genet 1:511–515
Yu S, Pritchard M, Kremer E, Lynch M, Nancarrow J, Baker E, Holman K, Mulley JC, Warren ST, Schlessinger D, Sutherland R, Richards RI (1991) Fragile X genotype characterized by an unstable region of DNA. Science 252:1179–1181
Yu S, Mulley J, Loesch D, Turner G, Donnelly A, Gedeon A, Hillen D, Kremer E, Lynch M, Pritchard M, Sutherland GR, Richards RI (1992) Fragile-X-syndrome: unique genetics of the heritable unstable element. Am J Hum Genet 50:968–980
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Buyle, S., Reyniers, E., Vits, L. et al. Founder effect in a Belgian-Dutch fragile X population. Hum Genet 92, 269–272 (1993). https://doi.org/10.1007/BF00244471
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DOI: https://doi.org/10.1007/BF00244471