Preimplantation genetic diagnosis for complex chromosome rearrangements

Abstract

Complex chromosome rearrangements (CCR) are structural rearrangements that involve more than two breakpoints. The most common ones involve three chromosomes and three breakpoints, but double translocations can also occur. Theoretically, the potential for chromosome imbalance in the gametes of CCR carriers is higher than for simple translocations, and thus they are at an even higher risk of recurrent miscarriage. Preimplantation genetic diagnosis (PGD) has been shown to significantly reduce the risk of repeated pregnancy loss in translocation carriers, and thus it is well indicated for CCR. Here we describe different approaches for PGD of CCRs. After PGD of five couples carriers of CCR, only 6.4% of embryos were found normal or balanced, but the transfer of these six embryos into four couples, resulted in two pregnancies, one with normal non-identical twins, and the other with a balanced karyotype. Thus the implantation rate was 50%, and the pregnancy per retrieval was 40%, with 0% spontaneous abortions and 0% unbalanced offspring. This compares favorably with a prior history of spontaneous abortions, unbalanced offspring, and low fertility.

Sequential FISH allows the determination of the segregation outcome and the presence of numerical anomalies in spermatozoa from a t(1;8;2)(q42;p21;p15) carrier

“…Escudero et al [5] reported two normal/balanced embryos out of 22 diagnosed in a three-way translocation carrier. The couple achieved pregnancy and delivery of a child after five PGD cycles.…”

Increased IVF pregnancy rates after microarray preimplantation genetic diagnosis due to parental translocations

“…Individuals who carry a balanced translocation or inversion are known to have high rates of unbalanced gametes following meiotic segregation and are at great risk of producing embryos with unbalanced chromosome complements. These chromosome imbalances can lead to high rates of miscarriage, decreased fertility, and in some cases, the birth of children affected by congenital aberrations [Escudero et al 2008;Treff et al 2011].…”

Sperm FISH and chromatin integrity in spermatozoa from a t(6;10;11) carrier

“…According to the structure of the rearrangement, CCRs can be categorised into four main types (Escudero et al 2008, Gruchy et al 2010, Kang et al 2010, Pellestor et al 2011a, Madan 2012. The first type is the simplest in structure and includes an equal number of breakpoints and of chromosomes involved in the CCR, a so-called three-way rearrangement with three non-homologous chromosomes with one breakpoint each.…”

“…Such a high frequency indicates an increased risk of reproductive failure, such as miscarriages (50-100%) (Batista et al 1994). Moreover, only 5-10% of CCRs are recognised de novo in prenatal diagnosis (Giardino et al 2006, Escudero et al 2008, Lim et al 2008). In such cases, an estimated value of 3.5% per every chromosome breakpoint in CCRs has been adapted as a reliable and predictable value for the determination of the risk factor in offspring (Madan 2012).…”