title: Fragile X AGG analysis provides new risk predictions for 45-69 repeat alleles.
abstract: We investigated the effect of AGG interruptions on fragile X repeat instability upon transmission of fragile X intermediate and small premutation alleles with 45-69 CGG repeats. The FMR1 repeat structure was determined for 375 mothers, 48 fathers, and 538 offspring (457 maternal and 81 paternal transmissions) using a novel PCR assay to determine repeat length and AGG interruptions. The number of AGG interruptions and the length of uninterrupted CGG repeats at the 3' end were correlated with repeat instability on transmission. Maternal alleles with no AGGs conferred the greatest risk for unstable transmissions. All nine full mutation expansions were inherited from maternal alleles with no AGGs. Furthermore, the magnitude of repeat expansion was larger for alleles lacking AGG interruptions. Transmissions from paternal alleles with no AGGs also exhibited greater instability than those with one or more AGGs. Our results demonstrate that characterization of the AGG structure within the FMR1 repeat allows more accurate risk estimates of repeat instability and expansion to full mutations for intermediate and small premutation alleles.
authors: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA. sallynolin@gmail.com
authors: Sarah L
authors: SL
authors: Nolin
authors: Sachin
authors: S
authors: Sah
authors: Anne
authors: A
authors: Glicksman
authors: Stephanie L
authors: SL
authors: Sherman
authors: Emily
authors: E
authors: Allen
authors: Elizabeth
authors: E
authors: Berry-Kravis
authors: Flora
authors: F
authors: Tassone
authors: Carolyn
authors: C
authors: Yrigollen
authors: Amy
authors: A
authors: Cronister
authors: Marcia
authors: M
authors: Jodah
authors: Nicole
authors: N
authors: Ersalesi
authors: Carl
authors: C
authors: Dobkin
authors: W Ted
authors: WT
authors: Brown
authors: Raghav
authors: R
authors: Shroff
authors: Gary J
authors: GJ
authors: Latham
authors: Andrew G
authors: AG
authors: Hadd
mesh_terms: D000483:Alleles; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000175:diagnosis* / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D009154:Mutation; D011379:Prognosis; D012306:Risk; D019680:Trinucleotide Repeat Expansion
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human