Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles

被引:271
作者
Nolin, SL
Brown, WT
Glicksman, A
Houck, GE
Gargano, AD
Sullivan, A
Biancalana, V
Bröndum-Nielsen, K
Hjalgrim, H
Holinski-Feder, E
Kooy, F
Longshore, J
Macpherson, J
Mandel, JL
Matthijs, G
Rousseau, F
Steinbach, P
Väisänen, ML
von Koskull, H
Sherman, SL
机构
[1] New York State Inst Basic Res Dev Disabil, Dept Human Genet, Staten Isl, NY 10314 USA
[2] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA
[3] Fac Med Strasbourg, Lab Diagnost Genet, Strasbourg, France
[4] Ctr Hosp Reg Univ, Strasbourg, France
[5] John F Kennedy Inst, DK-2600 Glostrup, Denmark
[6] Univ Munich, Abt Med Genet, Munich, Germany
[7] Univ Antwerp, Dept Med Genet, B-2020 Antwerp, Belgium
[8] Greenwood Genet Ctr, Greenwood, SC 29646 USA
[9] Wessex Reg Genet Lab, Salisbury, Wilts, England
[10] Catholic Univ Louvain, Ctr Human Genet, B-3000 Louvain, Belgium
[11] Univ Laval, Quebec City, PQ, Canada
[12] Univ Ulm, Abt Humangenet, Ulm, Germany
[13] Oulu Univ Hosp, Dept Clin Genet, Oulu, Finland
[14] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland
关键词
D O I
10.1086/367713
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The CGG repeat in the 5 untranslated region of the fragile X mental retardation 1 gene (FMR1) exhibits remarkable instability upon transmission from mothers with premutation alleles. A collaboration of 13 laboratories in eight countries was established to examine four issues concerning FMR1 CGG-repeat instability among females with premutation (similar to55-200 repeats) and intermediate (similar to46-60 repeats) alleles. Our central findings were as follows: (1) The smallest premutation alleles that expanded to a full mutation (>200 repeats) in one generation contained 59 repeats; sequence analysis of the 59-repeat alleles from these two females revealed no AGG interruptions within the FMR1 CGG repeat. (2) When we corrected for ascertainment and recalculated the risks of expansion to a full mutation, we found that the risks for premutation alleles with <100 repeats were lower than those previously published. (3) When we examined the possible influence of sex of offspring on transmission of a full mutation-by analysis of 567 prenatal fragile X studies of 448 mothers with premutation and full-mutation alleles-we found no significant differences in the proportion of full-mutation alleles in male or female fetuses. (4) When we examined 136 transmissions of intermediate alleles from 92 mothers with no family history of fragile X, we found that, in contrast to the instability observed in families with fragile X, most (99/136 [72.8%]) transmissions of intermediate alleles were stable. The unstable transmissions (37/136 [27.2%]) in these families included both expansions and contractions in repeat size. The instability increased with the larger intermediate alleles (19% for 49-54 repeats, 30.9% for 55-59, and 80% for 60-65 repeats). These studies should allow improved risk assessments for genetic counseling of women with premutation or intermediate-size alleles.
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页码:454 / 464
页数:11
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