Familial transmission of the FMR1 CGG repeat.
To better define the nature of FMR1 CGG-repeat expansions, changes in allele sizes for 191 families with fragile X and for 33 families with gray-zone repeats (40-60) were analyzed. Expansion of the fragile X chromosome to the full mutation was seen in 13.4% of offspring from premutation mothers with 56-59 repeats, 20.6% of those with 60-69 repeats, 57.8% of those with 70-79 repeats, 72.9% of those with 80-89 repeats, and 97.3% of those with 90-199 repeats. For premutation fathers, the majority (62%) of their daughters had a larger repeat number, while a few had either a smaller (22%) or the same (16%) repeat number, compared with their fathers' sizes. However, daughters with a smaller repeat number were observed only if their fathers had > or = 80 repeats. Fifteen (39.5%) of 38 such daughters carried a smaller repeat than did their fathers. We observed that a similar repeat number was inherited more often than expected by chance, among the members of a sibship segregating fragile X. This familial clustering, observed in the offspring of both males and females with a premutation, implies there may be an additional factor, independent of parental repeat size, that influences CGG-repeat instability. Instability in gray-zone allele transmissions was observed in 25% of alleles with 50-60 CGGs but in <8% of those with 40-49 CGGs. Examination of gray-zone allele organization revealed that long tracts of pure CGGs (>34) are not always unstably transmitted. These results raise new questions regarding the familial factors that may determine transmission expansions.
Nolin
S L
SL
Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Lewis
F A
FA
Ye
L L
LL
Houck
G E
GE
Glicksman
A E
AE
Limprasert
P
P
Li
S Y
SY
Zhong
N
N
Ashley
A E
AE
Feingold
E
E
Sherman
S L
SL
Brown
W T
WT
D000483:Alleles; D000704:Analysis of Variance; D002873:Chromosome Fragility; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018911:Trinucleotide Repeats / Q000235:genetics*