Urakawa Tatsuki, Ozawa Junichi, Tanaka Masato, Narusawa Hiromune, Matsuoka Kentaro, Fukami Maki, Nagasaki Keisuke, Kagami Masayo
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, Nagasaki University, Japan.
Department of Pediatrics, Graduate School of Medicine, Niigata University, Japan.
Eur J Med Genet. 2023 Jan;66(1):104671. doi: 10.1016/j.ejmg.2022.104671. Epub 2022 Nov 17.
Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder with characteristic features, such as overgrowth, macroglossia, and exomphalos. Hypomethylation of the KCNQ1OT1:TSS-differentially methylated region (DMR) on the 11p15.5 imprinted region is the most common etiology of BWS. KCNQ1 on 11p15.5 is expressed from the maternally inherited allele in most tissues, but is biparentally expressed in the heart, and maternal KCNQ1 transcription is required to establish the maternal DNA imprint in the KCNQ1OT1:TSS-DMR. Loss of function variants in KCNQ1 result in long QT syndrome type 1 (LQT1). To date, eight patients with BWS due to KCNQ1 splice variants or structural abnormalities involving KCNQ1 but not the KCNQ1OT1:TSS-DMR have been reported (KCNQ1-BWS), and four of them had LQT1. We report a Japanese boy with BWS and LQT1 presenting with extreme hypomethylation of the KCNQ1OT1:TSS-DMR caused by a de novo 215-kb deletion including KCNQ1 but not the KCNQ1OT1:TSS-DMR on the maternal allele. He was born by emergency cesarean section due to suspicion of placental abruption at 30 weeks of gestation. His birth weight and length were +1.6 SD and +1.0 SD, respectively. His placental weight was +3.9 SD, and histological examination of his placenta was consistent with mesenchymal dysplasia. He had BWS clinical features, including macroglossia, ear creases and pits, body asymmetry, and rectus abdominis muscle dehiscence, and BWS was therefore diagnosed. LQT1 was first noticed at three months in a preoperative examination for lingual frenectomy. The summarized data of our patient and the previously reported eight patients in KCNQ1-BWS showed more frequent and earlier preterm births and smaller sized birth weight in KCNQ1-BWS cases than those with BWS caused by epimutation of the KCNQ1OT1:TSS-DMR. In addition, in five of nine patients with KCNQ1-BWS, LQT1 was detected, and two of them were identified at school age. In our patient and in another single case with LQT1, the LQT1 was not detected early despite neonatal ECG monitoring. For BWS patients with extreme hypomethylation of the KCNQ1OT1:TSS-DMR, searching for CNVs involving KCNQ1 and mutation screening for KCNQ1 should be considered together with periodic ECG monitoring. (338/500 words).
贝克威思-维德曼综合征（BWS）是一种具有特征性表现的印记紊乱疾病，如过度生长、巨舌症和脐膨出。11p15.5印记区域的KCNQ1OT1:TSS差异甲基化区域（DMR）低甲基化是BWS最常见的病因。11p15.5上的KCNQ1在大多数组织中从母系遗传的等位基因表达，但在心脏中双亲表达，并且母系KCNQ1转录是在KCNQ1OT1:TSS-DMR中建立母系DNA印记所必需的。KCNQ1功能丧失变异导致1型长QT综合征（LQT1）。迄今为止，已有8例因KCNQ1剪接变异或涉及KCNQ1但不涉及KCNQ1OT1:TSS-DMR的结构异常导致的BWS患者被报道（KCNQ1-BWS），其中4例患有LQT1。我们报告了一名患有BWS和LQT1的日本男孩，其母系等位基因上发生了一个215 kb的新发缺失，包括KCNQ1但不包括KCNQ1OT1:TSS-DMR，导致KCNQ1OT1:TSS-DMR极度低甲基化。他因妊娠30周时怀疑胎盘早剥而紧急剖宫产出生。他的出生体重和身长分别高于均值1.6标准差和1.0标准差。他的胎盘重量高于均值3.9标准差，胎盘组织学检查符合间叶发育异常。他具有BWS的临床特征，包括巨舌症、耳部褶皱和凹陷、身体不对称以及腹直肌裂开，因此被诊断为BWS。LQT1最早在三个月时舌系带切除术的术前检查中被发现。我们的患者以及先前报道的8例KCNQ1-BWS患者的汇总数据显示，与由KCNQ1OT1:TSS-DMR表观突变导致的BWS病例相比，KCNQ1-BWS病例的早产更频繁且更早，出生体重更小。此外，在9例KCNQ1-BWS患者中的例5中检测到LQT1，其中2例在学龄期被发现。在我们的患者以及另一例LQT1单病例中，尽管进行了新生儿心电图监测，但LQT1并未早期被检测到。对于KCNQ1OT1:TSS-DMR极度低甲基化的BWS患者，应考虑寻找涉及KCNQ1的拷贝数变异（CNV）和KCNQ1的突变筛查，并定期进行心电图监测。（338/500字）
Clin Epigenetics. 2018-8-30
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