Meiotic recombination observed through preimplantation genetic testing for two X-linked conditions: first reported...

To report a case of human meiotic recombination illustrated by the use of preimplantation genetic testing for monogenic disorders (PGT-M) in a female patient heterozygous for pathogenic variants in cis on the X chromosome, highlighting the potential implications of meiotic recombination when performing PGT-M for ≥2 variants located on the same chromosome of a parental haplotype.

Case report.

A G3P3 female patient, heterozygous for two X-linked pathogenic variants in cis, involving the OTC and STS genes, sought to conceive an unaffected pregnancy through the use of in vitro fertilization (IVF) with PGT-M on the basis of her history of having a son with ornithine transcarbamylase (OTC) deficiency and steroid sulfatase (STS) deficiency who died following a hyperammonemic crisis.

Preimplantation genetic testing for monogenic disorders for maternal OTC and STS variants, previously determined to be in cis in the patient and her deceased son.

Proportion of embryos that screened positive by PGT-M for both, neither, or only one of the maternal OTC and STS variants.

Preimplantation genetic testing for monogenic disorders was performed on 13 embryos. Nine (69%) embryos screened positive for both or neither of the maternal OTC (c.788A>G) and STS (1.6Mb deletion of Xp22.31) variants, as expected given their configuration in cis. Four embryos (31%) screened positive for only one variant (either the OTC or STS variant), suggestive of X-linked meiotic recombination occurring at the frequency predicted on the basis of the genomic distance between STS and OTC. The patient transferred a female euploid embryo low-risk by PGT-M for the maternal OTC and STS variants, and declined prenatal diagnostic testing via chorionic villus sampling or amniocentesis. The patient delivered a healthy term female infant via repeat Cesarean section.

Meiotic recombination may lead to unanticipated results when using PGT-M to screen embryos for multiple monogenic conditions involving variants on the same chromosome. Detection of linked variants when screening embryos for genetic conditions (i.e., instead of direct genotyping) could lead to a false-negative result. This case underscores the importance of involving medical geneticists and genetic counselors to facilitate comprehensive and accurate clinical genetic evaluations, variant interpretation, confirmatory testing, and risk assessment to promote informed reproductive decision-making.