chain reaction (PCR) assays that are robust and sensitive. Next‐generation sequencing (NGS) has allowed for accurate identification and transfer of euploid embryos (PGT for aneuploidies (PGT‐A)1).
PGT‐M was initially applied for the same indications as prenatal diagnosis,2–4 but was then expanded to conditions that had never been considered, such as late‐onset diseases with genetic predisposition and preimplantation HLA typing with or without testing for genetic disorders.5–7
PGT represents a natural evolution of the genetic disease prevention technology, from a period with limited genetic counseling and no prenatal diagnosis or treatment to a time when many options, including PGT, have become available.8 Furthermore, PGT has been applied in order to improve access to the new treatment methods for some severe conditions by stem cell transplantation, for which no traditional treatment approaches are available. The impact of PGT and stem cell treatment on existing policies for the prevention of genetic disease (see Chapter 36) is clear from the increasing use of PGT to avoid unnecessary termination of many wanted pregnancies and for preimplantation HLA typing.
Approaches to preimplantation genetic testing
When prenatal genetic diagnosis was first considered in perspective, in 1984, the World Health Organization (WHO) emphasized the relevance of developing earlier approaches for genetic analysis with the possibility of diagnosis before implantation.9, 10 The following possibilities for PGT were mentioned: genetic analysis of the first or second polar bodies and embryo biopsy at the cleavage or blastocyst stage.10, 11 However, these approaches became possible only after introduction of the PCR assay12 and success in micromanipulation and embryo biopsy.
First attempts at PGT were undertaken in mammalian embryos over 30 years ago,13–18 when it was demonstrated that cells could be removed from mammalian preimplantation embryos and analyzed successfully without destroying the viability of the embryo in in vitro fertilization (IVF). PGT for human genetic disease was first demonstrated by Handyside et al.19 for X‐linked diseases and by Verlinsky et al.20 for autosomal recessive disorders. Tens of thousands of children without detectable birth defects have been born following these procedures,21–25 demonstrating that PGT can be performed safely in humans. Initially, PGT was based on polar body sampling and embryo biopsy at the cleavage stage, but the present standard shifted to blastocyst biopsy. The polar body approach is still, however, the only possibility for the ethnic groups where no embryos micromanipulation is allowed. The Preimplantation Genetic Diagnosis International Society (PGDIS) and the European Society of Human Reproduction and Embryology (ESHRE) Consortium have published an extensive set of best practice guidelines for PGT.26, 27 These recommendations cover PGT organization, genetic and treatment‐related counseling, psychologic evaluation, patient selection, all applicable technical issues, and quality control. The developments of preconception and PGT and the existing problems in the application of these early approaches to clinical practice are presented in this chapter, based on our 30 years' experience of over 22,000 PGT cycles, including 15,700 PGT‐A, 491 PGT‐HLA, and 6,778 PGT‐M, involving a spectrum of, approximately, 600 different monogenic conditions (Table 2.1).
Table 2.1 List of conditions for which preimplantation genetic testing (PGT) was performed and PGT‐M outcome: 30 years of original experience.
| Conditions | Gene | Type of inheritance | No. patients | No. cycles | No. embryo transfers | No. embryos transferred | Pregnancy % | No. deliveries |
|---|---|---|---|---|---|---|---|---|
| 3‐Hydroxyisobutyryl‐CoA hydrolase deficiency (HIBCHD) | HIBCH | AR | 1 | 1 | 1 | 2 | 0 | 0 |
| 3‐Methylglutaconic aciduria with deafness, encephalopathy, and Leigh‐like syndrome (MEGDEL) | SERAC1 | AR | 1 | 1 | 1 | 1 | 0 | 0 |
| Achondroplasia (ACH) | FGFR3 | AD | 8 | 17 | 11 | 14 | 7 | 6 |
| Achromatopsia 2 (ACHM2) | CNGA3 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Achromatopsia 3 (ACHM3) | CNGB3 | AR | 3 | 4 | 4 | 5 | 2 | 2 |
| Acromesomelic dysplasia, Maroteaux type (AMDM) | NPR2 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Acyl‐CoA dehydrogenase, medium‐chain, deficiency | ACADM | AR | 3 | 8 | 7 | 14 | 4 | 4 |
| Acyl‐CoA dehydrogenase, very long‐chain; (ACADVL) | ACADVL | AR | 5 | 6 | 6 | 11 | 2 | 2 |
| Adrenal hyperplasia, congenital, due to 21‐hydroxylase deficiency | CYP21A2 | AR | 23 | 34 | 26 | 42 | 17 | 17 |
|
Adrenoleukodystrophy
|
