台湾贝克威思-维德曼综合征患者的表观基因型、基因型和表型分析。

Epigenotype, genotype, and phenotype analysis of patients in Taiwan with Beckwith-Wiedemann syndrome.

作者信息

Lin Hsiang-Yu, Chuang Chih-Kuang, Tu Ru-Yi, Fang Yi-Ya, Su Yi-Ning, Chen Chih-Ping, Chang Chia-Ying, Liu Hsi-Che, Chu Tzu-Hung, Niu Dau-Ming, Lin Shuan-Pei

机构信息

Department of Medicine, Mackay Medical College, New Taipei City, Taiwan; Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan; Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan; Medical College, Fu-Jen Catholic University, Taipei, Taiwan; Institute of Biotechnology, National Taipei University of Technology, Taipei, Taiwan.

出版信息

Mol Genet Metab. 2016 Sep;119(1-2):8-13. doi: 10.1016/j.ymgme.2016.07.003. Epub 2016 Jul 12.

DOI:10.1016/j.ymgme.2016.07.003

PMID:27436784

Abstract

BACKGROUND

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder predisposing to tumorigenesis that results from abnormal expression or function of imprinted genes of chromosome 11p15.5.

METHODS

Forty-seven patients in Taiwan with clinical suspicion of BWS were referred for diagnostic testing based on methylation profiling of H19-associated imprinting center (IC) 1 and KCNQ1OT1-associated IC2 using high-resolution melting analysis, multiplex ligation-dependent probe amplification, or high-resolution quantitative methylation profiling.

RESULTS

Twenty-eight patients received a clinical diagnosis of BWS (the presence of 3 major features or 2 major features and at least 1 minor feature), 18 had suspected BWS (the presence of at least 1 major feature), and 1 had isolated Wilms' tumor. Nineteen patients were identified with IC2 hypomethylation (including 1 with isolated Wilms' tumor), 1 with IC1 hypermethylation, 2 with paternal uniparental disomy, and 1 with CDKN1C mutation. Several clinical features were found to be statistically different (P<0.05) between the 2 groups-clinical diagnosis of BWS (n=28) or suspected BWS (n=18)-including macroglossia, pre- or postnatal gigantism, abdominal wall defect, ear creases, facial nevus flammeus, BWS score, and the molecular diagnosis rate. Molecular lesion was detected in 81% of patients with the presence of three major features, compared with 33% and 28% of those with two or one major feature, respectively. The mean BWS score was 5.6 for 19 subjects with "IC2 hypomethylation", compared with 3.8 for 2 subjects with pUPD. The BWS score of one subject with CDKN1C mutation and one with IC1 hypermethylation was 6 and 7, respectively.

CONCLUSIONS

The BWS score was positively correlated with the molecular diagnosis rate (P<0.01). The BWS database of epigenotype, genotype, and phenotype is expected to promote better genetic counseling and medical care of these patients.

摘要

背景

贝克威思-维德曼综合征（BWS）是一种先天性过度生长疾病，易发生肿瘤，由11p15.5染色体印记基因的异常表达或功能引起。

方法

台湾地区47例临床怀疑患有BWS的患者，基于使用高分辨率熔解分析、多重连接依赖探针扩增或高分辨率定量甲基化分析对H19相关印记中心（IC）1和KCNQ1OT1相关IC2进行甲基化分析，接受诊断检测。

结果

28例患者获得BWS临床诊断（存在3项主要特征或2项主要特征及至少1项次要特征），18例疑似BWS（存在至少1项主要特征），1例患有孤立性肾母细胞瘤。19例患者被鉴定为IC2低甲基化（包括1例患有孤立性肾母细胞瘤），1例IC1高甲基化，2例父源单亲二体，1例CDKN1C突变。发现两组（BWS临床诊断组，n = 28；疑似BWS组，n = 18）之间的几个临床特征在统计学上存在差异（P < 0.05），包括巨舌症、产前或产后巨大症、腹壁缺损、耳部褶皱、面部火焰状痣、BWS评分和分子诊断率。在存在三项主要特征的患者中，81%检测到分子病变，相比之下，存在两项或一项主要特征的患者分别为33%和28%。19例“IC2低甲基化”受试者的平均BWS评分为5.6，相比之下，2例父源单亲二体受试者的评分为3.8。1例CDKN1C突变受试者和1例IC1高甲基化受试者的BWS评分分别为6和7。