APCAD: a new method for detection of aneuploidy and mosaicism in preimplantation embryos

Abstract Research question Can we reliably detect (mosaic) aneuploidy in preimplantation embryos after multiple displacement amplification and SNP detection, independent of haplotyping and copy number detection, with our new method 'Analysis of Parental Contribution for Aneuploidy Detection' or 'APCAD'? Design Our method is based on the maternal contribution, a parameter which reflects the proportion of DNA that is of maternal origin for a given chromosome or chromosome segment. A maternal contribution deviating from 50% for autosomes is strongly indicative for a (mosaic) chromosomal anomaly. We optimized the method using cell mixtures with varying ratios of euploid and aneuploid (47,XY,+21) lymphocytes. Next, we retrospectively measured the maternal contribution for all chromosomes from 349 Karyomapping samples. Results Retrospective analysis showed a very skewed maternal contribution ( 63.6%) in 57 out of 59 autosome meiotic trisomies and all autosome monosomies (n=57) with values close to what is theoretically expected. Thirty-two out of 7436 chromosomes for which no anomalies had been observed with Karyomapping showed a similarly skewed maternal contribution. Conclusions With our new method, APCAD, we measured the maternal contribution, which is an intuitive parameter independent of copy number detection. This method is useful to detect copy number neutral anomalies and can confirm diagnosis of (mosaic) aneuploidy detected based on copy number. In addition, mosaic and complete aneuploidy can be distinguished and the parent of origin for (mosaic) chromosome anomalies can be determined. Due to these benefits, the APCAD method has the potential to improve aneuploidy detection performed by comprehensive PGT methods.