title: Detecting AGG Interruptions in Male and Female FMR1 Premutation Carriers by Single-Molecule Sequencing.
abstract: The FMR1 gene contains an unstable CGG repeat in its 5' untranslated region. Premutation alleles range between 55 and 200 repeat units and confer a risk for developing fragile X-associated tremor/ataxia syndrome or fragile X-associated primary ovarian insufficiency. Furthermore, the premutation allele often expands to a full mutation during female germline transmission giving rise to the fragile X syndrome. The risk for a premutation to expand depends mainly on the number of CGG units and the presence of AGG interruptions in the CGG repeat. Unfortunately, the detection of AGG interruptions is hampered by technical difficulties. Here, we demonstrate that single-molecule sequencing enables the determination of not only the repeat size, but also the complete repeat sequence including AGG interruptions in male and female alleles with repeats ranging from 45 to 100 CGG units. We envision this method will facilitate research and diagnostic analysis of the FMR1 repeat expansion.
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Simon
authors.initials: S
authors.lastname: Ardui
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Valerie
authors.initials: V
authors.lastname: Race
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Alena
authors.initials: A
authors.lastname: Zablotskaya
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Hestand
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
mesh_terms: D001259:Ataxia / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D014202:Tremor / Q000175:diagnosis / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human
keywords: AGG interruption; CGG repeat; fragile X syndrome; gray-zone repeats; premutation repeats; repeat expansion disease; single-molecule sequencing