Increased transmission of intermediate alleles of the FMR1 gene compared with normal alleles among female heterozygotes

Fragile X syndrome (Fra X) is the most common heritable disease accounting for mental retardation and is caused by an expanded CGG repeat in the first exon of the FMR1 gene, Previous studies have shown an increased fertility rate among fragile X carrier mothers and a preponderance of mentally retard ed boys among the male offspring. In this study, we examined the transmissi on of the intermediate allele in the lower range of CGG repeats in carrier mothers found randomly in a screening program of the normal population. me tested 10,587 healthy women with no family history of mental retardation an d identified 138 (1.3%) who were carriers of the intermediate allele (51-20 0 CG;GI repeats). Of these, 107 underwent prenatal testing during 108 pregn ancies for Fra X in the fetus. Of the 108 pregnancies, the abnormal allele was transmitted in 67 (segregation ratio = 0,62, P < 0.012), We found a sig nificant increase in the transmission of the abnormal allele by mothers who had between 51 and 60 repeats (segregation ratio = 0.69 [P < 0.007] for th e group with 51-55 repeats, and 0.74 [P < 0.04] for the group with 56-60 re peats), but no increase by mothers who had more than 61 repeats, This sugge sts a genetic advantage for the abnormal allele in the 51- to 60-repeat ran ge, (C) 2000 Wiley-Liss, Inc.