First validated method for distinguishing normal from balanced translocation carrier embryos

Abstract

Carriers of balanced translocations often wish to prevent inheritance in their offspring in order for their children to eventually avoid the same reproductive challenges. Although identifying unbalanced embryos has been possible for many years, current PGS methods are unable to reliably distinguish a truly normal embryo from one that carries a balanced translocation. The present study was conducted to validate a method that provides the opportunity to make this distinction for the first time. Prospective blinded. A series of translocation carrier couples that underwent IVF with SNP array based PGD were included. Embryos that were transferred in these cases could have been balanced or normal. SNP array analysis was performed on parental DNA and unbalanced embryos from each case to define informative SNPs whose alleles were linked with the derivative chromosomes (phasing). The transferred sibling embryo array data were then evaluated at the informative SNP loci to predict whether they were truly normal (did not inherit the derivative chromosomes) or translocation carriers. IRB approval was obtained to perform conventional karyotyping on the newborns in order to establish the true genetic status of the original transferred embryo (balanced or normal). Embryonic SNP array predictions were then compared to the newborn karyotypes obtained. Phasing SNPs using unbalanced embryos allowed accurate prediction of whether transferred embryos were balanced translocation carriers or truly normal in all 10 cases completed to date (100% concordance with conventional karyotyping of newborns). This study demonstrates the validity of the first method capable of distinguishing normal from balanced translocation carrier embryos. The only prerequisite is the availability of parental DNA and unbalanced IVF embryos, making the method applicable to the majority of carrier couples. In addition, the SNP array platform allows simultaneous evaluation of comprehensive chromosome screening for aneuploidy, in parallel, from the same biopsy. Future work will involve prospective predictions to select normal embryos with subsequent karyotyping of the resulting newborns.