Uniparental disomy (UPD) in the human blastocyst is exceedingly rare

Abstract

UPD results from the inheritance of 2 copies of a chromosome from the same parent instead of 1 from each. UPD can lead to severe disease as a result of improper imprinting or homozygosity for recessive disorders. This study develops a validated method to detect UPD in human blastocysts and estimates its frequency using a large sample size. Observational. Cell lines with previously established whole chromosome uniparental heterodisomy (UPhD) or isodisomy (UPiD) were used as controls to establish SNP array-based criteria for UPD identification on 5-cell samples. UPiD, the presence of 2 identical chromosomes from one parent, was identified by analysis of loss of heterozygosity (LOH). UPhD, the presence of 2 homologous chromosomes from one parent, was identified by evaluating similarity of genotypes to parental DNA. Thresholds for each type of UPD were then applied to SNP array data from trophectoderm biopsies previously used for comprehensive chromosome screening. Mean LOH probabilities and percent similarity to parental genotypes successfully identified true positive UPiD and UPhD chromosomes in controls. Following application of defined thresholds, 2 of 3,401 (0.06%) blastocysts were found to possess UPiD; one was 46,XX,UPD(22) and the other was 49,XX,UPD(6),+7,+13,+15. Zero of 803 blastocysts, for which parental DNA was available, were found to possess UPhD. The overall frequency of UPD in the human blastocyst was therefore 0.06%. This validated screening method indicates that UPD is extremely rare and suggests that routine screening during PGD may not be necessary. Given the exceedingly low prevalence, it is very unlikely that UPD is a physiologically meaningful phenomenon and may not be used to explain clinical findings such as putative self-correction of monosomic embryos. Furthermore, previous data on cleavage stage embryos suggesting high rates of UPD may need to be reconsidered given the lack of validation of the detection methods used in those studies.