Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization
Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization
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DOI：
10.1002/humu.22824
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发表时间：
2015-09-01
期刊：
影响因子：
3.9
通讯作者：
Rossignol, Sylvie
中科院分区：
文献类型：
--
作者：
Brioude, Frederic;Netchine, Irene;Rossignol, Sylvie
Beckwith-Wiedemann综合征（BWS）是一种与巨舌症、腹壁缺损、内脏肿大和儿童肿瘤高风险相关的印记性疾病。分子异常大多是表观遗传的;然而，CDKN 1C突变涉及8%的病例，包括散发性和家族性形式。我们的目的是描述具有CDKN 1C突变的BWS患者的表型，并开发CDKN 1C突变的功能测试。对于每一位先证者，我们对表现出BWS表型（包括腹壁缺陷，但没有11 p15甲基化缺陷）的患者中CDKN 1C的三个外显子和内含子-外显子边界进行了测序。我们开发了一种基于流式细胞术的功能测试。我们在38个家系（50名患者和7名胎儿）中发现了37个突变。对父母样本的分析显示，除了一个突变是从母亲那里遗传的外，所有的突变都是测试过的。与其他33个突变相比，4个错义突变导致的表型不太严重（外切突变频率较低）。发生了以下4例肿瘤：1例神经母细胞瘤、1例神经节神经母细胞瘤、1例黑色素瘤和1例急性淋巴细胞白血病。由CDKN 1C突变引起的BWS病例并不罕见。CDKN 1C测序应用于表现为腹壁缺损或腭裂但无11 p15甲基化缺陷或身体不对称的BWS患者，或家族性BWS病例。(C)2015 Wiley Periodicals，Inc.
Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron-exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS. (C) 2015 Wiley Periodicals, Inc.