Reproductive risks and preimplantation genetic testing intervention for X-autosome translocation carriers

Abstract Research question What is the genetic cause of multiple congenital disabilities in a girl with maternal balanced X-autosome translocation [t(X-A)]? Is the preimplantation genetic testing (PGT) strategy, that distinguishing noncarrier from euploid/balanced embryos and prioritized transfer, an effective and applicable way for couples with t(X-A)? Design Karyotype analysis, whole-exome sequencing (WES), and X inactivation analysis were performed for the girl with congenital cardiac anomaly, language defect, and mild neurodevelopmental delay. PGT based on next-generation sequencing following the microdissecting junction region to distinguish noncarrier and carrier embryos were used in three couples with female t(X-A) carrier (Cases 1-3). Results The girl carried a maternal balanced translocation 46,X,t(X;1)(q28;p31.1). WES revealed no monogenic mutation related to her phenotype, but she carried a rare skewed inactivation of the translocation X chromosome and spread to the adjacent interstitial 1p segment, contrary to her mother. All translocation breakpoints of Cases 1-3 were successfully identified and each couple underwent one PGT cycle. Thirty oocytes were retrieved, and 13 blastocysts were eligible for biopsy, of which 6 (46.15%) embryos were balanced and only 4 were noncarriers. Three frozen embryo transfers with noncarrier embryos resulted in the birth of two healthy children (one girl and one boy), who were subsequently confirmed to have normal karyotypes. Conclusions We reported a girl with multiple congenital disabilities associated with maternal balanced t(X-A) and verified that the distinction of noncarrier and carrier embryos is an effective and applicable strategy to avoid transferring genetic and reproductive risks to the offspring of t(X-A) carriers.