Medical Faculty, Institute for Human Genetics and Genome Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.
Clin Epigenetics. 2023 Mar 1;15(1):35. doi: 10.1186/s13148-023-01453-5.
Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking.
Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype-phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues.
Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants contribute to MLID.
印迹障碍（ImpDis）包括由单等位基因和亲本来源依赖性表达基因的异常调控引起的疾病。ImpDis 患者的一个特征性分子变化是疾病特异性位点的异常甲基化特征，而在特定差异甲基化区域（DMR）没有明显的 DNA 变化。然而，越来越多的关于多基因印迹障碍（MLIDs）的报道，即在同一患者的不同 DMR 中出现异常甲基化。这些 MLIDs 在特定的 ImpDis 患者中占很大比例，有几项报道表明，致病性母源效应变异在其发病机制中起着核心作用，影响卵母细胞和早期胚胎的成熟。尽管已经有几项关于 MLID 的流行率和分子原因的研究，但仍缺乏包含基因组和甲基化数据的同质数据集。
基于 36 名 MLID 患者的队列，我们在这里同时展示了来自下一代测序（NGS，ImprintSeq）方法和全外显子组测序（WES）的甲基化数据。甲基化数据的汇编并没有揭示出疾病特异性的 MLID 表观遗传特征，也没有明显的表型修饰倾向。事实上，这种缺乏表型-表型相关性可能与印迹缺陷的镶嵌分布及其在特定组织中的功能相关性有关。
由于基于 NGS 的方法具有更高的敏感性，我们建议在 ImpDis 患者表现出不寻常的表型但常规检测为 MLID 阴性的情况下，在参考中心提供 ImprintSeq。通过 WES，除了已经知道的母源效应变异外，在患者和母源外显子组中都不能确定其他 MLID 原因。在 WES 结果为阴性的情况下，目前尚不清楚环境因素或未检测到的遗传变异在多大程度上导致了 MLID。
