Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, D-52074, Aachen, Germany.
Clin Epigenetics. 2019 Feb 15;11(1):30. doi: 10.1186/s13148-019-0629-x.
Deletions of the imprinting centre 1 (IC1) in 11p15.5 are rare and their clinical significance is not only influenced by their parental origin but also by their exact genomic localization. In case the maternal IC1 allele is affected, the deletion is associated with the overgrowth disorder Beckwith-Wiedemann syndrome (BWS) and a gain of methylation (GOM) of the IC1. The consequences of deletions of the paternal IC1 allele depend on the localization and probably the binding sites of methylation-specific DNA-binding factors affected by the change. It has been suggested that distal deletions of the paternal allele are associated with a normal IC1 methylation and phenotype, whereas proximal alterations cause a loss of methylation (LOM) and Silver-Russell syndrome (SRS) features.
In a patient referred for molecular BWS testing and his family, a deletion within the IC1 was identified by MLPA. It was associated with a GOM, corresponding to the transmission of the alteration via the maternal germline. Accordingly, the deletion was also detectable in the maternal grandmother, but here the paternal chromosome 11p15.5 was affected and a IC1 LOM was observed. By nanopore sequencing, the localization of the deletion could be precisely determined.
We report for the first time both GOM and LOM of the IC1 in the same family, caused by transmission of a 2.2-kb deletion in 11p15.5. Nanopore sequencing allowed the precise characterization of the change by long-read sequencing and thereby provides further insights in the regulation of imprinting in the IC1.
11p15.5 印迹中心 1（IC1）缺失非常罕见，其临床意义不仅受其亲本来源影响，还受其确切的基因组定位影响。如果母系 IC1 等位基因受到影响，缺失与过度生长障碍 Beckwith-Wiedemann 综合征（BWS）和 IC1 的甲基化增益（GOM）相关。父系 IC1 等位基因缺失的后果取决于受变化影响的甲基化特异性 DNA 结合因子的定位和可能的结合位点。有人提出，父系等位基因的远端缺失与正常的 IC1 甲基化和表型相关，而近端改变则导致甲基化丢失（LOM）和 Silver-Russell 综合征（SRS）特征。
在一名接受分子 BWS 检测的患者及其家族中，通过 MLPA 鉴定出 IC1 内的缺失。它与 GOM 相关，这与通过母系生殖系传递的改变相对应。因此，在患者的祖母中也可以检测到缺失，但这里父系 11p15.5 受到影响，观察到 IC1 LOM。通过纳米孔测序，可以精确确定缺失的定位。
我们首次在同一家庭中报告了 IC1 的 GOM 和 LOM，这是由 11p15.5 中 2.2kb 缺失的传递引起的。纳米孔测序通过长读测序精确地描述了变化，从而为 IC1 印迹调控提供了进一步的见解。
