PGT-SR: A Comprehensive Overview and a Requiem for the Interchromosomal Effect

Abstract

Preimplantation genetic testing for structural rearrangements (PGT-SR) was one of the first applications of PGT, with initial cases being worked up in the Delhanty lab. It is the least well-known of the various forms of PGT but nonetheless provides effective treatment for many carrier couples. Structural chromosomal rearrangements (SRs) lead to infertility, repeated implantation failure, pregnancy loss, and congenitally affected children, despite the balanced parent carrier having no obvious phenotype. A high risk of generating chromosomally unbalanced gametes and embryos is the rationale for PGT-SR, aiming to select for those that are chromosomally normal, or at least balanced like the carrier parent. PGT-SR largely uses the same technology as PGT-A, i.e., initially FISH, superseded by array CGH, SNP arrays, Karyomapping, and, most recently, next-generation sequencing (NGS). Trophectoderm biopsy is now the most widely used sampling approach of all PGT variants, though there are prospects for non-invasive methods. In PGT-SR, the most significant limiting factor is the availability of normal or balanced embryo(s) for transfer. Factors directly affecting this are rearrangement type, chromosomes involved, and sex of the carrier parent. De novo aneuploidy, especially for older mothers, is a common limiting factor. PGT-SR studies provide a wealth of information, much of which can be useful to genetic counselors and the patients they treat. It is applicable in the fundamental study of basic chromosomal biology, in particular the purported existence of an interchromosomal effect (ICE). An ICE means essentially that the existence of one chromosomal defect (e.g., brought about by malsegregation of translocation chromosomes) can perpetuate the existence of others (e.g., de novo aneuploidy). Recent large cohort studies of PGT-SR patients seem, however, to have laid this notion to rest, at least for human embryonic development. Unless new evidence comes to light, this comprehensive review should serve as a requiem.

Keywords

• PGT-SR
• chromosome
• translocation
• inversion
• Robertsonian
• reciprocal