LIKELIHOOD FOR REACHING EMBRYO TRANSFER FOLLOWING EXCLUSION-BASED NON-DISCLOSURE PREIMPLANTATION GENETIC TESTING FOR MONOGENIC CONDITIONS (PGT-M)

Abstract

Non-disclosure (ND) preimplantation genetic testing (PGT) for monogenic disorders (PGT-M) via in vitro fertilization (IVF) is an option for individuals at risk for having a late-onset dominant condition. One method involves testing the patient for a familial mutation without disclosing the results, and blinding them to whether their embryos are tested via PGT-M with concurrent PGT for aneuploidy (PGT-A) if they have the mutation, or via PGT-A only if they do not. Exclusion-based testing is an alternate method which does not require the patient’s mutation status to be known. Rather, by determining which of the patient’s chromosome homologs with the gene of interest was inherited from their affected parent, embryos that inherit that copy of the chromosome are excluded from transfer due to the potential risk for inheriting the mutation. Exclusion-based testing eliminates the risk for accidental disclosure of the patient’s mutation status but may exclude unaffected embryos from transfer if the patient does not have the familial mutation. Patients may consider cryopreservation of potentially at-risk embryos in case they pursue testing for themselves at a later time. In this study, we review the likelihood of unaffected and euploid embryo results using exclusion-based ND testing. Retrospective analysis of trophectoderm (TE) biopsy results from IVF patients referred for exclusion-based ND PGT-M with concurrent PGT-A. For each case, a mutation/clinical diagnosis report for the affected relative and samples from the couple and the at-risk patient’s parent(s) were required. TE biopsies were shipped to a lab for genotyping using Illumina Cyto12 SNP-based microarrays with informatics. Twenty-five patients underwent exclusion-based ND PGT-M for 7 disorders (Huntington’s Disease (HD), n=19; Spinocerebellar ataxia (SCA) type 3, n=1; SCA type 6, n=1; Polycystic kidney disease, n=1; Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), n=1; Familial TTR amyloidosis, n=1; Creutzfeldt-Jakob disease, n=1). A total of 273 TE samples from 46 IVF cycles were tested (average of 5.9 embryos/cycle, range 1-21). Average maternal age was 33.1 years (range 26.2–41.9 years). 73.9% (34/46) of cycles had at least one euploid and unaffected embryo. Analysis by maternal age groups indicated that the chance of having at least one euploid and unaffected embryo was 83.3% (5/6) for <30 years, 76.7% (23/30) for 30-34 years, and 60% (6/10) for women ≥35 years. Exclusion-based ND testing avoids the risk of accidental disclosure of a patient’s mutation status, while allowing a relatively high rate of having an embryo for transfer after a single IVF cycle. This information may be useful for counseling patients considering ND exclusion-based PGT-M and discussing the potential need for additional IVF cycles in order to reach transfer, especially for women of advanced maternal age. Although ND exclusion-based testing is most commonly performed for HD, here we demonstrate that this method can be utilized for other dominant late-onset conditions.