Clinical significance and mechanisms associated with segmental UPD

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.

Case Report: Decrypting an interchromosomal insertion associated with Marfan’s syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants

“…This condition has been reported in aging, cancer, and increasingly in congenital disorders. In all cases, variants with a lower cell fitness, disease variants, or chromosomal imbalances can be removed by somatic recombination, resulting in segmental uniparental disomy and CN-LoH ( Loh et al, 2020 ; Papenhausen et al, 2021 ). CN-LoHs are detected through trio SNP analysis and are unquestionable of postzygotic origin.…”

olecular cytogenetic and cytopostgenomic analysis of the human genome

“…Molecular karyotyping by SNP array was performed in 600 cases from the karyotyped cohort. The protocol of SNP array was repeatedly described previously [40][41][42][43]. Bioinformatic analyses were carried out by an original methodology, which included systems genome (variome) analysis, data fusion, "CNV launder-ing" and pathway-based prioritization of genomic variations.…”

“…Focusing on karyotyping data obtained from studying 8556 individuals with neurodevelopmental disorders and congenital malformations, allowed us to select a very specific group of individuals (n=600; ~7%), who require molecular karyotyping and extended bioinformatic analysis of genome data. SNP array was selected as a technique of choice, inasmuch as it allows detecting chromosomal imbalances and CNVs at the highest resolution [40][41][42][43] and segmental uniparental disomies within imprinted loci [40,47]. Thus, a heuristic algorithm for comprehensive genome analysis for medical genetics does require both karyotyping (classical cytogenetics) and molecular karyotyping by SNP array.…”