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Fragile X AGG analysis provides new risk predictions for 45–69 repeat alleles
Author(s) -
Nolin Sarah L.,
Sah Sachin,
Glicksman Anne,
Sherman Stephanie L.,
Allen Emily,
BerryKravis Elizabeth,
Tassone Flora,
Yrigollen Carolyn,
Cronister Amy,
Jodah Marcia,
Ersalesi Nicole,
Dobkin Carl,
Brown W. Ted,
Shroff Raghav,
Latham Gary J.,
Hadd Andrew G.
Publication year - 2013
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.35833
Subject(s) - allele , fmr1 , genetics , fragile x syndrome , biology , offspring , fragile x , trinucleotide repeat expansion , microsatellite , gene , pregnancy
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. © 2013 Wiley Periodicals, Inc.