Fragile X AGG analysis provides new risk predictions for 45-69 repeat alleles

• Type of Material: Article
• Authors: Emily Allen, Emory University; Stephanie Sherman, Emory University; Sarah L. Nolin, New York State Institute for Basic Research in Developmental Disabilities; Sachin Sah, Asuragen Inc; Anne Glicksman, New York State Institute for Basic Research in Developmental Disabilities; Elizabeth Berry-Kravis, Rush University; Flora Tassone, University of California Davis; Carolyn Yrigollen, University of California Davis; Amy Cronister, Integrated Genetics, Westborough; Marcia Jodah, Integrated Genetics, Westborough; Nicole Ersalesi, New York State Institute for Basic Research in Developmental Disabilities; Carl Dobkin, New York State Institute for Basic Research in Developmental Disabilities; W. Ted Brown, New York State Institute for Basic Research in Developmental Disabilities; Raghav Shroff, Asuragen Inc; Gary J. Latham, Asuragen Inc; Andrew G. Hadd, Asuragen Inc
• Language: English
• Date: 2013-04-01
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/ajmg.a.35833
• Title of Journal or Parent Work: American Journal of Medical Genetics Part A
• Volume: 161A
• Issue: 4
• Start Page: 771
• End Page: 778
• Grant/Funding Information: This work was supported in part by the New York State Institute for Basic Research in Developmental Disabilities, the NYS Office of People with Developmental Disabilities and by National Institutes of Health grants R01 HD29909, P30 HD24064 (S.L.S and E.A.), and HD02274 (F.T.), 2R44HD066953-02 (AGH, GJL and SS).
• Keywords: Genetics & Heredity; IDENTIFICATION; trinucleotide repeat instability; Science & Technology; PREMUTATION; INSTABILITY; Life Sciences & Biomedicine; DNA; RANGE; CGG REPEAT; fragile X; FMR1; EXPANDED ALLELES; FMR1 GENE; PREVALENCE; EXPANSION
• Research Categories: Chemistry, Biochemistry; Health Sciences, Medicine and Surgery; Biology, Genetics

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.