PURPOSE Beckwith-Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM. METHODS We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect. RESULTS We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission. CONCLUSION These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.

中文翻译：

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KCNQ1 的转录改变与 Beckwith-Wiedemann 基因座中的印迹甲基化缺陷相关。

目的 Beckwith-Wiedemann 综合征 (BWS) 是由染色体 11p15.5 的印记基因簇失调引起的发育障碍，通常与位于 KCNQ1 内含子 10 的印记中心 2 (IC2) 的甲基化缺失 (LOM) 相关。为了揭示这些表观突变背后的病因机制，我们搜索了与 IC2 LOM 相关的遗传变异。方法 我们寻找显示 BWS 和长 QT 综合征 (LQTS) 临床特征的病例，这通常与 KCNQ1 变异有关。通过基因组分析和靶向测序鉴定了致病变异。进行了功能实验以将这些致病变异与印记缺陷联系起来。结果我们发现了三个罕见的病例，其中完整的 IC2 LOM 与 KCNQ1 变体的母体传播有关，其中两个被证明影响IC2上游的KCNQ1转录。由于 KCNQ1 单倍体不足，这些变异也会导致母系和父系传播的 LQTS。结这对遗传咨询很重要。