Preimplantation genetic diagnosis for fragile X syndrome: is there increased transmission of abnormal FMR1 alleles among female heterozygotes?

Background: Fragile X syndrome is caused by a CGG triplet-repeat expansion mutation in the FMR1 gene. Previous studies have shown increased transmission of abnormal alleles in the 51-60 repeat range. This study was undertaken to evaluate the performance of preimplantation genetic diagnosis (PGD) for fragile X, and to assess the transmission rate of the abnormal FMR1 alleles in this setting.

Method: The study included 18 fragile X carriers who applied for PGD. FMR1 CGG repeats ranged from 70 to 300. PGD was performed using multiplex-nested PCR, with simultaneous amplification of the CGG repeat region and several polymorphic markers, and sex chromosome markers.

Results: Four patients had a poor ovarian response, and could not undergo PGD. The remaining 14 patients underwent 47 PGD cycles. A total of 565 oocytes were aspirated. Of the 386 embryos that were successfully biopsied, 18 (6.4%) could not be analyzed due to amplification failure, and 12 (4.3%) had sex chromosomal abnormalities. Of the remaining 250 embryos, the abnormal allele was transmitted to 124 embryos (49.6%) compared to 126 (50.4%) for the normal allele. This difference was not statistically significant. Only embryos carrying the normal allele were transferred, resulting in 7 clinical pregnancies (18% per embryo transfer).

Conclusions: Our results demonstrate that PGD for fragile X is feasible, and that carriers transmit the abnormal allele at the same frequency as the normal allele.