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.

中文翻译：

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节段性UPD相关的临床意义和机制

全染色体单亲二体 (UPD) 已被充分记录，其机制在很大程度上已被了解。然而，节段性受限UPD（segUPD）的病因尚不明确。在确认（> 300）全染色体 UPD 病例的 10 年期间，我们在产前和产后样本中鉴定了 86 个节段性病例。由于与 Beckwith-Wiedemann 综合征相关的体细胞选择，其中 32 例在 11p 显示马赛克节段性 UPD。这项研究侧重于与其余病例相关的明显机制，其中许多似乎代表了基因组失衡的纠正，例如缺失和衍生染色体。在某些情况下，节段性 UPD 与额外基因组失衡的产生有关，而在其他情况下，它显然导致整倍体的恢复。使用非侵入性产前检测 (NIPT)、绒毛膜绒毛取样 (CVS) 和来自同一次怀孕的羊水样本进行的多项测试揭示了校正的时间证据和 1p 处的“热点”。尽管在许多情况下，基因组失衡在分析的组织中被剂量“修复”，但由于原始失衡的早期发育影响或由于其在其他组织中的持续存在，临床效果可以持续。此外，如果配子中没有发生校正，这些个体的后代就会有复发的风险。提出了家族微阵列等位基因模式，将配子校正的缺乏与体细胞衍生的性腺嵌合体区分开来。