Segmental aneuploidy in human blastocysts: a qualitative and quantitative overview

Abstract

Background Microarray-based and next generation sequencing (NGS) technologies have revealed that segmental aneuploidy is frequently present in human oocytes, cleavage-stage embryos and blastocysts. However, very little research has analyzed the type, size, chromosomal distribution and topography of the chromosomal segments at the different stages of development. Methods This is a retrospective study of 822 PGT-A (preimplantation genetic test for aneuploidies) performed on trophectoderm samples from 3565 blastocysts biopsied between January 2016 and April 2017. The cycles in question had been initiated for varying clinical indications. Samples were analyzed by next generation sequencing-based technology. Segmental aneuploidies were evaluated when fragment size was > 5 Mb. Blastocysts presenting a single segmental aneuploidy (SSA), without any additional whole-chromosome gain/loss, were statistically analyzed for incidence, type, size and chromosomal emplacement. Segment sizes relative to the whole chromosome or arm (chromosome- and arm-ratios) were also studied. Results 8.4% (299/3565) of blastocysts exhibited segmental aneuploidy for one or more chromosomes, some of which were associated with whole-chromosome aneuploidy while others were not. Nearly half of them (4.5%: 159/3565 of blastocysts) exhibited pure-SSA, meaning that a single chromosome was affected by a SSA. Segments were more frequent in medium-sized metacentric or submetacentric chromosomes and particularly in q-chrmosome arms, variables that were related to trophectoderm quality. SSA size was related to a greater extent to chromosome number and the arm affected than it was to SSA type. In absolute values (Mb), SSA size was larger in large chromosomes. However, the SSA:chromosome ratio was constant across all chromosomes and never exceeded 50% of the chromosome. Conclusions SSA frequency is chromosome- and topographically dependent, and its incidence is not related to clinical or embryological factors, but rather to trophectoderm quality. SSA might be originated by chromosome instability in response to chromothripsis, bias introduced by the biopsy and/or iatrogenic effects. Trial registration Retrospectively registered.

Next-Generation Sequencing Revealed that High Proportion of Human Embryos Resulted from Donor Eggs Are Segmental Chromosome Abnormal

“…It has been reported that approximately ~6-15% of blastocysts from human IVF have segmental abnormalities when evaluated by current PGT-A methods with different analysis platforms [25,27,28]. The incidence of blastocysts with only segmental abnormalities is about 2.4%-7.5% of all samples examined [25,[27][28][29].…”

Preimplantation Genetic Testing for Chromosomal Abnormalities: Aneuploidy, Mosaicism, and Structural Rearrangements

“…Generally, DSBs elicit a DNA repair mechanism, and failure to execute it typically activates the apoptotic process [73]. Those pathways are often compromised in preimplantation embryos, which are characterized by rapid cell division, compromised repair mechanisms, lax cell cycle checkpoints, and deregulated apoptosis [74]. When a cell 'repairs' a DSB incorrectly, it can result in duplication or deletion of the segment containing the break.…”

“…Segmental abnormalities can occur in any chromosome, their incidence across the genome largely correlates with chromosomal size, and the frequency of losses and gains is roughly equal [75]. One possible outlier is the high incidence of segmental gains in the q-arm of chromosome (Chr) 9 [74,75]. A study has described loci in the genome of preimplantation embryos with higher likelihood of segmental abnormalities, possibly related to heterochromatic composition of those regions [70].…”

“…When only considering instances with no concomitant whole chromosome aneuploidy, the incidence of blastocysts with segmental losses or gains is 2.4%-7.5% [11,70,74,75]. Incidence of segmental abnormalities in blastocysts do not correlate with medical indication or patient age [70,74,75]. Segmental abnormalities are thought to account for 6% of clinical miscarriages [77] and affect close to 0.05% of newborns [78].…”

“…Approximately ~6%–15% of ART-created blastocysts contain segmental abnormalities when evaluated by current PGT-A methods with the described resolution, either exclusively or in conjunction with whole chromosome aneuploidies [ 70 , 74 , 75 ]. When only considering instances with no concomitant whole chromosome aneuploidy, the incidence of blastocysts with segmental losses or gains is ~2.4%–7.5% [ 11 , 70 , 74 , 75 ]. Incidence of segmental abnormalities in blastocysts do not correlate with medical indication or patient age [ 70 , 74 , 75 ].…”