title: Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles.
abstract: 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 (approximately 55-200 repeats) and intermediate (approximately 46-60 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.
authors.affiliation: Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA. snolin@mindspring.com
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Nolin
authors.forename: W Ted
authors.initials: WT
authors.lastname: Brown
authors.forename: Anne
authors.initials: A
authors.lastname: Glicksman
authors.forename: George E
authors.initials: GE
authors.lastname: Houck
authors.forename: Alice D
authors.initials: AD
authors.lastname: Gargano
authors.forename: Amy
authors.initials: A
authors.lastname: Sullivan
authors.forename: Valérie
authors.initials: V
authors.lastname: Biancalana
authors.forename: Karen
authors.initials: K
authors.lastname: Bröndum-Nielsen
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Frank
authors.initials: F
authors.lastname: Kooy
authors.forename: John
authors.initials: J
authors.lastname: Longshore
authors.forename: James
authors.initials: J
authors.lastname: Macpherson
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.forename: Francois
authors.initials: F
authors.lastname: Rousseau
authors.forename: Peter
authors.initials: P
authors.lastname: Steinbach
authors.forename: Marja-Leena
authors.initials: ML
authors.lastname: Väisänen
authors.forename: Harriet
authors.initials: H
authors.lastname: von Koskull
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Sherman
mesh_terms: D020121:5' Untranslated Regions; D000483:Alleles; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D012306:Risk; D012737:Sex Factors; D035781:Siblings; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions