What can karyomapping teach us about segmental mosaicism and mechanisms of its origin

Introduction Due to the rapid development in the PGT field, new and challenging issues including increased detection rates of embryos with segmental mosaicism have emerged. On the other hand, this rapid development brings us better technologies to address these issues. Even though karyomapping (SNP based array) is limited in aneuploidy testing and enables detection of high-level mosaic only, it provides us with interesting information whether mosaic aneuploidies affect mostly maternal or paternal chromosomes. We focused our attention oncomparing affected chromosomes in both mosaic segmentals and mosaic whole chromosomal aneuploidies with segmentals and whole chromosomal aneuploidies. Materials & methods The incidence and origin of chromosomal aneuploidies (including whole chromosomal aneuploidy, mosaic whole chromosomal aneuploidy, segmentals and mosaic segmentals) were assesed in 1206 trophectoderm biopsies. More than 97% (1172/1206) of samples were successfully analyzed by karyomapping (Illumina - HumanKaryomap 12 SNP bead chips, BlueFuse Multi software) in 249 PGT-M for various single gene conditions. All chromosomes of all embryos were evaluated on a B-llele frequency chart (BAF), a logR chart and haploblock charts. Mitotic aneuploidies including mosaics were called if BAF and logR chart were consistent, but aneuploidy was not indicated on a haploblock chart. Results At least one whole chromosomal aneuploidy was detected in 29.3% of the trophectoderm biopsies, while a segmental aneuploidy was detected in 5.7% of the trophectoderm biopsies. A uniparental disomy was detected 4 times (0.34%). Interestingly, our results reveal that segmental aneuploidies predominantly affect chromosomes of paternal origin (p< 0.0001) in comparison to whole chromosomal aneuploidies that more frequently affect chromosomes or maternal origin (p< 0.0001). Interestingly, a thorough analysis of our SNP data indicates that also mosaic segmentals affect mainly paternal chromosomes (24/31; 77.4%). Regarding mosaic whole chromosomal aneuploidies, SNP data indicates that mitotic errors affects predominantly maternal chromosomes (17/25; 68%). In addition to this, the frequency of meiosis I and meiosis II errors was established in errors with both parental homologs (BPH). MI errors were observed to be more frequent (70.4%; 126/179) than MII errors (29.6%; 53/179). Conclusions Our results show that both segmental aneuploidies and mosaic segmental aneuploidy affect mainly paternal chromosomes. The fact that mosaic segmentals are mostly detected in chromosomes of paternal origin as well as in full segmental aneuploidies strongly indicates that both originate in post-zygotic embryonal development and represent the same biological phenomenon rather than an artefact of whole genome amplification or SNP detection. Our findings support the hypothesis, that fragmentation during spermatogenesis might be the main reason why most of the segmental changes affect paternal chromosomes. Unrepaired fragments may be lost either during fertilization or during the first cell divisions in the early embryonic development, resulting in segmental loss and mosaic segmental loss. Further studies are needed for a better understanding of the biological significance of segmental mosaics and the clinical impact on the PGT outcome.