35. Runs of homozygosity (ROH) reveal that segmental-UPD is associated with the repair of genomic imbalance

Abstract

Uniparental disomy (UPD) in the context of whole chromosome non-disjunction mediated trisomy or monosomy is well documented with mechanisms largely understood. In contrast, the etiology of segmental UPD (segUPD) existing in only a portion of a chromosome pair, primarily evinced by a terminal absence of heterozygosity, occurs rarely and the etiology is not well documented. In the course of confirming (300) cases of whole chromosome UPD using single nucleotide polymorphism (SNP) microarrays to detect runs of homozygosity (ROH) associated with UPD we identified 62 cases of segUPD in prenatal and postnatal samples. Nearly half of these cases were due to positive selection based Beckwith-Wiedemann syndrome 11p15 imprinting imbalance. We highlight a subset of the remaining cases to show that segUPD occurs secondarily to mitotic recombination based correction of genomic imbalances that include deletions, translocation derivative chromosomes and terminal deletions with contiguous duplications. Non-invasive prenatal testing (NIPT), CVS, placental, amniotic fluid and peripheral blood samples taken from several individuals at multiple times show temporal correction of aberrations during fetal development. Although the various genetic lesions are “repaired”, sustained clinical effects might still be present because the original imbalance may have affected early development, may still be present in some cells or the resulting seg-UPD may unmask a recessive disorder. In the case of genomic rearrangements consisting of terminal deletions with contiguous duplications, we hypothesize that genomic repair processes restore euploidy if initiated proximal to the duplication, but result in a triplication and terminal segUPD if initiated at the “end” of the inverted duplication. Importantly, these studies suggest that the incidence of segUPD mediated correction is underestimated, and may explain the etiology of clinical phenotypes that are undetected by CGH based microarray analysis and whole exome sequencing studies.