TY - JOUR
T1 - Fragile X AGG analysis provides new risk predictions for 45-69 repeat alleles
AU - Nolin, Sarah L.
AU - Sah, Sachin
AU - Glicksman, Anne
AU - Sherman, Stephanie L.
AU - Allen, Emily
AU - Berry-Kravis, Elizabeth
AU - Tassone, Flora
AU - Yrigollen, Carolyn
AU - Cronister, Amy
AU - Jodah, Marcia
AU - Ersalesi, Nicole
AU - Dobkin, Carl
AU - Brown, W. Ted
AU - Shroff, Raghav
AU - Latham, Gary J.
AU - Hadd, Andrew G.
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - FMR1
KW - Fragile X
KW - Trinucleotide repeat instability
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U2 - 10.1002/ajmg.a.35833
DO - 10.1002/ajmg.a.35833
M3 - Article
C2 - 23444167
AN - SCOPUS:84875525912
SN - 1552-4825
VL - 161
SP - 771
EP - 778
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 4
ER -