Abstract
Whole chromosome uniparental disomy (UPD) has been well documented with mechanisms largely understood. However, the etiology of segmental limited UPD (segUPD) is not as clear. In a 10-year period of confirming (> 300) cases of whole chromosome UPD, we identified 86 segmental cases in both prenatal and postnatal samples. Thirty-two of these cases showed mosaic segmental UPD at 11p due to somatic selection associated with Beckwith–Wiedemann syndrome. This study focuses on apparent mechanisms associated with the remaining cases, many of which appear to represent corrections of genomic imbalance such as deletions and derivative chromosomes. In some cases, segmental UPD was associated with the generation of additional genomic imbalance while in others it apparently resulted in restoration of euploidy. Multiple tests utilizing noninvasive prenatal testing (NIPT), chorionic villus sampling (CVS) and amniotic fluid samples from the same pregnancy revealed temporal evidence of correction and a “hotspot” at 1p. Although in many cases the genomic imbalance was dosage “repaired” in the analyzed tissue, clinical effects could be sustained due to early developmental effects of the original imbalance or due to its continued existence in other tissues. In addition, if correction did not occur in the gametes there would be recurrence risks for the offspring of those individuals. Familial microarray allele patterns are presented that differentiate lack of gamete correction from somatic derived gonadal mosaicism. These results suggest that the incidence of segUPD mediated correction is underestimated and may explain the etiology of some clinical phenotypes which are undetected by routine microarray analysis and many exome sequencing studies.
Highlights
Whole chromosome uniparental disomy (UPD), the inheritance of both homologues from one parent, has been confirmed as primarily originating from somatic corrections of meiotically-derived trisomy or monosomy [1]
More than a third (32/85) of the cases of segmental limited UPD (segUPD) identified were associated with terminal mosaic runs of homozygosity (ROH) of various lengths and percentages on the p arm of chromosome 11 (Fig. 4), the phenotypes of which were consistent with Beckwith–Wiedemann syndrome (BWS)
This study offers evidence that segUPD has occurred secondarily to genomic corrections of deletions, derivative chromosomes, and terminal deletions contiguous with copy number gains
Summary
Whole chromosome uniparental disomy (UPD), the inheritance of both homologues from one parent, has been confirmed as primarily originating from somatic corrections of meiotically-derived trisomy or monosomy [1]. Reports of copy-neutral segmentally-restricted UPD are much rarer at about 0.03%, excluding Beckwith–Wiedemann syndrome (BWS) cases associated with imprinted paternal growth advantage at 11p15.5 [10, 11]. SegUPD is especially common in cancer and, in those studies, it is generally referred to as copy-neutral loss of heterozygosity (CN-LOH). Constitutional segUPD is typically detected in single nucleotide polymorphism (SNP) chromosomal microarray analysis (CMA) as a long terminal ROH in a single chromosome (Fig. 1) that, in molecular follow-up, shows allelic exclusions from one parent in the ROH and biparental allele inheritance in the rest of the chromosome. Consanguinity can present a diagnostic problem for detection of segUPD, but is associated with ROH in multiple chromosomes that are usually not found exclusively in terminal regions [12]. The American College of Medical Genetics has proposed guidelines for diagnostic testing of suspected whole chromosome UPD and segUPD [13]
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