Meiotic Recombination on Display Through Preimplantation Genetic Testing for Two X-Linked Disorders
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
We describe a female found to be heterozygous for pathogenic variants associated with ornithine transcarbamylase (OTC) deficiency and steroid sulfatase (STS) deficiency, and discuss the demonstrated implications of meiotic recombination observed via preimplantation genetic testing for monogenic disorders (PGT-M) of multiple variants located on the X chromosome.
Case Presentation
A 36-year-old gravida 2 para 2 female was referred for preconception genetic counseling after the death of her son at 3 days of life after he presented with hyperammonemia and ichthyosis. The pregnancy was notable for negative OTC carrier screening and low estriol on maternal serum screening, followed by a maternal chromosomal microarray which identified a single copy loss of the STS gene due to an approximately 1.6 Mb heterozygous deletion on Xp22.31.
Diagnostic Workup
Phenotype-informed clinical genome sequencing of the patient's son reported a hemizygous likely pathogenic variant in OTC (NM_000531.6: c.788A>G; p.Asp263Gly). The patient was confirmed to be heterozygous for the familial OTC variant via retrospective unmasking of her previous carrier screening results, followed by targeted variant testing. Clinical suspicion for ichthyosis prompted additional testing for her son which confirmed a maternally-inherited deletion on Xp22.31 that included the STS gene.
Treatment and Management
The patient decided to pursue in vitro fertilization (IVF) with PGT-M to screen embryos for the familial OTC and STS variants which were found to be in cis in her son. In total, 13 embryos were created and screened. Nine embryos screened positive for both or neither of the OTC and STS variants, suggestive of their configuration on the same allele (in cis). However, 4 embryos screened positive for only one variant, suggesting the OTC and STS variants are in trans in these embryos, demonstrative of X-linked meiotic recombination versus a less likely repeatedly inaccurate PGT-M result. To assess this further, the distance between the OTC and STS genes was calculated using centimorgans (cM), a unit of measure for the frequency of genetic recombination. The OTC and STS genes are approximately 31 cM apart, equating to an approximately 31% chance of recombination between OTC and STS, consistent with the observed frequency (4/13) in this case.
Outcome and Follow-Up
Of the 13 embryos, 8 were euploid. The patient proceeded with transferring a female euploid embryo negative for both the maternal OTC and STS variants by PGT-M. Prenatal diagnostic testing via chorionic villus sampling or amniocentesis was offered to confirm the PGT-M results, which was declined.
Discussion
It is necessary to consider the potential for meiotic recombination when PGT-M is used to screen embryos for multiple genetic disorders on the same chromosome. Awareness of this possibility has clinical implications regarding the use of linked markers instead of direct genotyping to screen for genetic disorders. This case highlights the importance of involving medical geneticists and genetic counselors to ensure patients undergo comprehensive and accurate clinical genetic evaluations, variant interpretation, confirmatory testing, and risk assessment to facilitate informed reproductive choices.
Conclusion
Clinicians should consider the possibility of meiotic recombination when using PGT-M to screen embryos for multiple monogenic conditions involving genetic variants located on the same chromosome, or when using linked markers instead of direct genotyping to screen for genetic disorders.
We describe a female found to be heterozygous for pathogenic variants associated with ornithine transcarbamylase (OTC) deficiency and steroid sulfatase (STS) deficiency, and discuss the demonstrated implications of meiotic recombination observed via preimplantation genetic testing for monogenic disorders (PGT-M) of multiple variants located on the X chromosome.
Case Presentation
A 36-year-old gravida 2 para 2 female was referred for preconception genetic counseling after the death of her son at 3 days of life after he presented with hyperammonemia and ichthyosis. The pregnancy was notable for negative OTC carrier screening and low estriol on maternal serum screening, followed by a maternal chromosomal microarray which identified a single copy loss of the STS gene due to an approximately 1.6 Mb heterozygous deletion on Xp22.31.
Diagnostic Workup
Phenotype-informed clinical genome sequencing of the patient's son reported a hemizygous likely pathogenic variant in OTC (NM_000531.6: c.788A>G; p.Asp263Gly). The patient was confirmed to be heterozygous for the familial OTC variant via retrospective unmasking of her previous carrier screening results, followed by targeted variant testing. Clinical suspicion for ichthyosis prompted additional testing for her son which confirmed a maternally-inherited deletion on Xp22.31 that included the STS gene.
Treatment and Management
The patient decided to pursue in vitro fertilization (IVF) with PGT-M to screen embryos for the familial OTC and STS variants which were found to be in cis in her son. In total, 13 embryos were created and screened. Nine embryos screened positive for both or neither of the OTC and STS variants, suggestive of their configuration on the same allele (in cis). However, 4 embryos screened positive for only one variant, suggesting the OTC and STS variants are in trans in these embryos, demonstrative of X-linked meiotic recombination versus a less likely repeatedly inaccurate PGT-M result. To assess this further, the distance between the OTC and STS genes was calculated using centimorgans (cM), a unit of measure for the frequency of genetic recombination. The OTC and STS genes are approximately 31 cM apart, equating to an approximately 31% chance of recombination between OTC and STS, consistent with the observed frequency (4/13) in this case.
Outcome and Follow-Up
Of the 13 embryos, 8 were euploid. The patient proceeded with transferring a female euploid embryo negative for both the maternal OTC and STS variants by PGT-M. Prenatal diagnostic testing via chorionic villus sampling or amniocentesis was offered to confirm the PGT-M results, which was declined.
Discussion
It is necessary to consider the potential for meiotic recombination when PGT-M is used to screen embryos for multiple genetic disorders on the same chromosome. Awareness of this possibility has clinical implications regarding the use of linked markers instead of direct genotyping to screen for genetic disorders. This case highlights the importance of involving medical geneticists and genetic counselors to ensure patients undergo comprehensive and accurate clinical genetic evaluations, variant interpretation, confirmatory testing, and risk assessment to facilitate informed reproductive choices.
Conclusion
Clinicians should consider the possibility of meiotic recombination when using PGT-M to screen embryos for multiple monogenic conditions involving genetic variants located on the same chromosome, or when using linked markers instead of direct genotyping to screen for genetic disorders.
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