Preimplantation genetic testing (PGT) is becoming more common within IVF programs. It is a way to perform genetic testing prior to embryo transfer. The ACOG document reviews the current nomenclature and requirements for confirmatory testing later in pregnancy.

WHAT IS IT?

• Most often, a biopsy is performed at the blastocyst stage, allowing 5 to 10 cells to be removed for further genetic testing. The goal is to identify unaffected embryos for transfer. There are different types of testing, depending on genetic disorder that is being assessed.

PGT-M: PGT for Monogenic Disorders

• This category covers single gene disorders | Mutations are at the level of individual genes
  • The embryo is tested for pathogenic variants
• PGT-M is an option for
  • Autosomal recessive or dominant single-gene disorders (e.g., cystic fibrosis): PGT-M is offered when a pregnancy has been identified to be at high risk through preconception carrier screening testing (either routine or known disorder within the family)
  • Heritable cancer syndromes: Patients may opt for PGT-M if a high risk pathogenic variant has been identified in genes (e.g., BRCA1/2) where mutations are known to predispose to cancers
  • HLA typing: PGT-M has been used to identify the HLA status of a fetus with the potential for cord blood or bone marrow matching for sick family members
• Caution
  • Current PGT-M techniques provide accurate results, but false positives and negatives may occur
  • Usually only specific genes and relevant variants are targeted
• Confirmatory CVS or amniocentesis should be offered

PGT-SR: PGT for for Structural Rearrangements

• This category covers structural rearrangements, which refer to genomic alterations at the chromosomal level
  • Examples of structural rearrangements: Translocations | Inversions | Deletions | Insertions
  • While the individual parent usually has a normal amount of DNA (e.g., a ‘balanced’ rearrangement), the fetus is at risk for gain or loss of chromosomal material that may occur during meiosis
  • Genetic counseling prior to pregnancy is recommended for individuals with structural rearrangements and should include a discussion regarding the option of PGT-SR
• Caution
  • Current methods identify overall amount of DNA
  • Some parental translocations may result in both chromosome copies being inherited from the same parent, leading to ‘imprinting’ errors
  • PGT-SR tests for overall amount of DNA, not parental source and, therefore, cannot currently exclude the possibility of disorders due to imprinting

PGT-A: PGT for Aneuploidy

• PGT-A screens for whole whole chromosome abnormalities such as trisomy 21 (Down syndrome)
  • Current technologies can assess all chromosomes
• One of the goals of PGT-A has been to enhance the quality of embryos for transfer by sorting out those with aneuploidy
• Caution
  • Data has been inconsistent regarding clinical utility
  • ASRM does not currently recommend routine use of PGT-A to all infertile women

KEY POINTS:

Confirmatory Genetic Testing During Pregnancy

• Confirmatory testing is recommended for all women undergoing PGT
  • CVS or amniocentesis may be offered
• ACOG states

Traditional diagnostic testing or screening for aneuploidy should be offered to all patients who have had preimplantation genetic testing-aneuploidy, in accordance with recommendations for all pregnant patients

• Counseling should include the following key points
  • PGT currently cannot detect all microdeletions or microduplications, or new pathogenic variants
  • Children may still be born with birth defects despite normal PGT report either from genetic changes not covered by PGT or unrelated to single-gene or chromosomal abnormalities
• If a patient declines the option of confirmatory testing
  • Patients may opt for aneuploidy screening
  • Inform patients that screening is not the same as diagnostic testing and false negatives and false positives may occur

PGT-A and Mosaicism

• Mosaicism is a recognized limitation of PGT-A
  • A single embryo may have more than one cell line (e.g., one cell has 3 copied of chromosome 21 (i.e., Down syndrome), while another cell has a normal chromosomal complement
  • May occur in up to 20% of PGT-A
  • Some embryos with mosaicism may continue to delivery and result in normal infants at term, depending on the chromosomes that are involved | Pregnancy rates may be decreased
  • “Referral to a specialist with genetic training and expertise should be considered”
  • Patient should be “strongly encouraged” to opt for confirmatory testing during pregnancy

Learn More – Primary Sources:

ACOG Committee Opinion 799: Preimplantation Genetic Testing

ASRM: The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion

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