PGT-M With or Without Triplet Repeat Detection for Fragile X Syndrome

Abstract

Background: Fragile X syndrome (FraX) is the most common single gene cause of intellectual disability. It is caused by an unstable triplet repeat expansion in the Fragile X Mental Retardation 1 ( FMR1 ) gene. Female pre-mutation carriers are at-risk of passing a full-mutation onto their offspring, resulting in intellectual disability. A reproductive option to reduce the risk of having an affected child is Pre-implantation Genetic Testing for a monogenetic condition (PGT-M). Various methods exist to perform PGT-M for FraX. Aim: To explore the option of PGT-M with and without triplet repeat detection for FraX, consider the potential advantages and disadvantages of each approach, and examine the decision of six couples undertaking PGT-M for FraX through our service. Method: Patients were offered the choice of two testing methods of PGT-M for FraX. The first was haplotype analysis of markers linked to the FMR1 gene. The second was haplotype analysis of linked markers with simultaneous triplet repeat detection. Advantages and disadvantages of testing with and without triplet repeat detection were identified. Each couple’s clinical history and opinion regarding transfer of pre-mutation embryos were elicited. The couples final decision and reasoning was explored. Results: Despite differing clinical histories and opinions on whether they would transfer a pre-mutation embryo or not, all six couples decided to proceed with PGT-M for FraX with triplet repeat detection. Reasons given included maximising information, treatment options, and pregnancy rate. Conclusion: PGT-M for FraX should be offered with triplet repeat detection to improve the robustness of the diagnosis and to maximise patient choice. All couples decided to have PGT-M for FraX with triplet repeat detection which ultimately allows them to consider transfer of a pre-mutation embryo if no unaffected embryos are available for transfer.