title: Origins of the fragile X syndrome mutation.
abstract: The fragile X syndrome is a common cause of mental impairment. In view of the low reproductive fitness of affected males, the high incidence of the syndrome has been suggested to be the result of a high rate of new mutations occurring exclusively in the male germline. Extensive family studies, however, have failed to identify any cases of a new mutation. Alternatively, it has been suggested that a selective advantage of unaffected heterozygotes may, in part, explain the high incidence of the syndrome. Molecular investigations have shown that the syndrome is caused by the amplification of a CGG trinucleotide repeat in the FMR-1 gene which leads to the loss of gene expression. Further to this, genetic studies have suggested that there is evidence of linkage disequilibrium between the fragile X disease locus and flanking polymorphic markers. More recently, this analysis has been extended and has led to the observation that a large number of fragile X chromosomes appear to be lineage descendants of founder mutation events. Here, we present a study of the FRAXAC1 polymorphic marker in our patient cohort. We find that its allele distribution is strikingly different on fragile X chromosomes, confirming the earlier observations and giving further support to the suggestions of a fragile X founder effect.
authors.affiliation: Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: Hirst
authors.forename: S J
authors.initials: SJ
authors.lastname: Knight
authors.forename: Z
authors.initials: Z
authors.lastname: Christodoulou
authors.forename: P K
authors.initials: PK
authors.lastname: Grewal
authors.forename: J P
authors.initials: JP
authors.lastname: Fryns
authors.forename: K E
authors.initials: KE
authors.lastname: Davies
mesh_terms: D000483:Alleles; D005600:Fragile X Syndrome / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid