BACKGROUND A subset of individuals affected by imprinting disorders displays multi-locus imprinting disturbances (MLID). MLID has been associated with maternal-effect variants that alter the maintenance of methylation at germline-derived differentially methylated regions (gDMRs) in early embryogenesis. Pedigrees of individuals with MLID also include siblings with healthy phenotype. However, it is unknown if these healthy individuals have MLID themselves or if their methylation patterns differ from those associated with imprinting disorders, and in general, if MLID affects the clinical phenotype. METHODS We have investigated gDMR methylation by locus-specific and whole-genome analyses in a family with multiple pregnancy losses, a child with Beckwith-Wiedemann syndrome (BWS) and a further child with no clinical diagnosis of imprinting disorder or other pathologies. RESULTS We detected MLID with different methylation profiles in the BWS-affected and healthy siblings. Whole-exome sequencing demonstrated the presence of novel loss-of-function variants of NLRP5 in compound heterozygosity in the mother. The methylation profiles of the two siblings were compared with those of other cases with MLID and control groups by principal component analysis and unsupervised hierarchical clustering, but while their patterns were clearly separated from those of controls, we were unable to cluster those associated with specific clinical phenotypes among the MLID cases. CONCLUSION The identification of two novel maternal-effect variants of NLRP5 associated with poly-abortivity and MLID adds further evidence to the role of this gene in the maintenance of genomic imprinting in early embryos. Furthermore, our results demonstrate that within these pedigrees, MLID can also be present in the progeny with healthy phenotype, indicating that some sort of compensation occurs between altered imprinted loci in these individuals. The analysis of larger cohorts of patients with MLID is needed to formulate more accurate epigenotype-phenotype correlations.

中文翻译：

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与 NLRP5 的母体效应变异相关的多位点印记紊乱的表型变异范围从明显的印记障碍到明显健康的表型。

背景受印记障碍影响的个体子集表现出多位点印记障碍(MLID)。MLID 与母体效应变异有关，这些变异改变了早期胚胎发生中种系衍生的差异甲基化区域 (gDMR) 甲基化的维持。MLID 患者的家谱还包括具有健康表型的兄弟姐妹。然而，尚不清楚这些健康个体本身是否患有 MLID，或者他们的甲基化模式是否与印记障碍相关的甲基化模式不同，以及一般而言，MLID 是否影响临床表型。方法 我们通过位点特异性和全基因组分析研究了一个多胎流产家庭的 gDMR 甲基化，一名患有 Beckwith-Wiedemann 综合征 (BWS) 的儿童和一名没有临床诊断为印记障碍或其他病症的儿童。结果 我们在受 BWS 影响和健康的兄弟姐妹中检测到具有不同甲基化谱的 MLID。全外显子组测序表明在母亲的复合杂合性中存在新的 NLRP5 功能丧失变体。通过主成分分析和无监督层次聚类，将两个兄弟姐妹的甲基化谱与其他 MLID 病例和对照组的甲基化谱进行了比较，但虽然他们的模式与对照组明显分开，但我们无法将与特定临床相关的模式聚类MLID 病例中的表型。结论 鉴定出与多胎流产和 MLID 相关的两个新的 NLRP5 母体效应变体进一步证明了该基因在维持早期胚胎基因组印记中的作用。此外，我们的结果表明，在这些谱系中，MLID 也可以存在于具有健康表型的后代中，表明在这些个体中改变的印迹位点之间发生了某种补偿。需要对更大的 MLID 患者队列进行分析，以制定更准确的表观基因型-表型相关性。表明在这些个体中改变的印迹位点之间发生了某种补偿。需要对更大的 MLID 患者队列进行分析，以制定更准确的表观基因型-表型相关性。表明在这些个体中改变的印迹位点之间发生了某种补偿。需要对更大的 MLID 患者队列进行分析，以制定更准确的表观基因型-表型相关性。