title: Apparently unstable normal FMR1 alleles in nine developmentally delayed patients: implications for molecular diagnosis of the fragile X syndrome.
abstract: The Fragile X syndrome is a common form of X-linked mental retardation, affecting approximately 1 in 4,000 males. Since the discovery of the FMR1 gene responsible for the syndrome, molecular, rather than cytogenetic, diagnosis of Fragile X syndrome has become the gold standard. Numerous molecular diagnostic centers worldwide use PCR and Southern blotting to characterize the size of the CGG repeats within the gene, expansion of which has been shown to be associated with the vast majority of cases of Fragile X syndrome. Instability of this repeat through successive generations has been demonstrated in many patients and has been associated with numerous factors, including repeat length and molecular structure of the repeat. Nine males with normal-size alleles that exhibit repeat length instability by the presence of a second normal length distinct band by repeated PCR analysis from peripheral lymphocytes are reported. Many hypotheses addressing the reason for this apparent instability were tested without elucidating the underlying molecular causes, including cytogenetic analysis, sequence analysis of the repeat locus, and analysis of flanking dinucleotide repeat loci. All patients exhibited a normal complement of sex chromosomes by cytogenetic and molecular analysis. These results from the widely used PCR analysis illustrate an interesting molecular phenomenon and raise many questions relating to the factors and mechanisms involved in trinucleotide instability as well as having implications for the diagnostic testing of the Fragile X syndrome.
authors.affiliation: Department of Genetics, North York General Hosptial, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Tzountzouris
authors.forename: D
authors.initials: D
authors.lastname: Kennedy
authors.forename: M
authors.initials: M
authors.lastname: Skuterud
authors.forename: M
authors.initials: M
authors.lastname: Connolly-Wilson
authors.forename: J J
authors.initials: JJ
authors.lastname: Holden
authors.forename: C C
authors.initials: CC
authors.lastname: Lin
authors.forename: E
authors.initials: E
authors.lastname: Mak-Tam
authors.forename: M J
authors.initials: MJ
authors.lastname: Somerville
authors.forename: A M
authors.initials: AM
authors.lastname: Summers
authors.forename: D J
authors.initials: DJ
authors.lastname: Allingham-Hawkins
mesh_terms: D000483:Alleles; D015139:Blotting, Southern; D002648:Child; D020732:Cytogenetic Analysis; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D016601:RNA-Binding Proteins; D018911:Trinucleotide Repeats
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human