Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Nordrhein-Westfalen, Germany
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Nordrhein-Westfalen, Germany.
J Med Genet. 2021 Mar;58(3):173-176. doi: 10.1136/jmedgenet-2020-106868. Epub 2020 May 23.
The chromosomal region 11p15.5 harbours two imprinting centres (:IG-DMR/IC1, :TSS-DMR/IC2). Molecular alterations of the IC2 are associated with Beckwith-Wiedemann syndrome (BWS), whereas only single patients with growth retardation and Silver-Russell syndrome (SRS) features have been reported. CNVs in 11p15.5 account for less than 1% of patients with BWS and SRS, and they mainly consist of duplications of both ICs either affecting the maternal (SRS) or the paternal (BWS) allele. However, this correlation does not apply to smaller CNVs, which are associated with diverse clinical outcomes.
We identified a family with a 132 bp deletion within the gene, associated with growth retardation in case of paternal transmission but a normal phenotype when maternally inherited. Comparison of molecular and clinical data with cases from the literature helped to delineate its functional relevance.
Microdeletions within the paternal IC2 affecting the gene have been described in only five families, and they all include the differentially methylated region :TSS-DMR/IC2 and parts of the gene. However, these deletions have different impacts on the expression of both genes and the cell-cycle inhibitor . They thereby cause different phenotypes. The 132 bp deletion is the smallest deletion in the IC2 reported so far. It does not affect the IC2 methylation in general and the coding sequence of the gene. Thus, the deletion is only associated with a growth retardation phenotype when paternally transmitted but not with other clinical features in case of maternal inheritance as observed for larger deletions.
染色体 11p15.5 区域含有两个印迹中心（IG-DMR/IC1、TSS-DMR/IC2）。IC2 的分子改变与 Beckwith-Wiedemann 综合征（BWS）有关，而仅有少数生长迟缓且具有 Silver-Russell 综合征（SRS）特征的患者被报道。11p15.5 的 CNV 占 BWS 和 SRS 患者的比例不到 1%，它们主要由两个 IC 的重复组成，要么影响母系（SRS），要么影响父系（BWS）等位基因。然而，这种相关性并不适用于较小的 CNV，它们与多种临床表现相关。
我们鉴定了一个家族，其 基因内存在 132bp 的缺失，当父系遗传时与生长迟缓相关，但母系遗传时表现正常。将分子和临床数据与文献中的病例进行比较有助于阐明其功能相关性。
仅在五个家族中描述了影响父系 IC2 的 基因内的微缺失，它们都包含差异甲基化区域：TSS-DMR/IC2 和部分 基因。然而，这些缺失对两个基因和细胞周期抑制剂的表达有不同的影响。因此，当父系遗传时，132bp 的缺失仅与生长迟缓表型相关，而当母系遗传时，与其他临床特征无关，这与较大缺失的情况不同。132bp 的缺失是迄今为止报道的 IC2 中最小的缺失。它一般不会影响 IC2 的甲基化和 基因的编码序列。因此，当父系遗传时，缺失仅与生长迟缓表型相关，而当母系遗传时，如较大缺失一样，不会与其他临床特征相关。
