A genomic copy number variant analysis implicates the MBD5 and HNRNPU genes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion.
A genomic copy number variant analysis implicates the MBD5 and HNRNPU genes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion.
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基因组拷贝数变体分析暗示了中国婴儿痉挛儿童的MBD5和HNRNPU基因，并扩大了2q23.1缺失的临床谱。
DOI：
10.1186/1471-2350-15-62
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发表时间：
2014-05-29
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
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作者：
Du X;An Y;Yu L;Liu R;Qin Y;Guo X;Sun D;Zhou S;Wu B;Jiang YH;Wang Y
婴儿痉挛是一种特殊类型的癫痫性脑病，与严重的发育障碍有关。遗传因素与IS密切相关，然而，在大多数情况下，确切的遗传缺陷仍然未知。在西方国家，单个基因或拷贝数变异（CNVs）中的罕见突变与儿童IS有关。本研究的目的是剖析拷贝数变异在中国婴儿痉挛症儿童中的作用。我们使用Agilent人类基因组CGH微阵列180 K进行全基因组CNV检测。实时qPCR用于验证CNV。我们对个体CNVs进行了基因组和医学注释，以确定与IS相关的CNVs的致病性。我们在此报告了第一个全基因组的CNV分析与IS儿童，共检测14个CNV的队列中的47名中国儿童与IS。4个CNV（4/47 = 8.5%）（1q21.1增加; 1 q44，2q31.1和17 p13丢失）被认为是致病性的。17p13.3的CNV缺失包含PAFAH 1B 1（LIS 1），这是无脑畸形的致病基因。尽管1q21.1，1 q44和2q23.1的CNV先前已涉及广泛的临床特征，包括自闭症谱系障碍（ASD）和全身性癫痫发作，但我们的研究是第一份在初步诊断为IS的个体中识别它们的报告。1 q44区域的CNV缺失包含HNRNPU，这是最近通过IS儿童的全外显子组测序在IS中提出的强候选基因。2q23.1的CNV缺失包括MBD 5，MBD 5是一种甲基DNA结合蛋白，是ASD的致病基因，也是癫痫性脑病的候选基因。我们还报告了一个独特的临床表现，IS，小头畸形，智力残疾，并没有拇与2q23.1缺失的情况下。我们的研究结果强烈支持CNVs在婴儿痉挛症中的作用，并扩大了与2q23.1缺失相关的临床谱。特别是，我们的研究涉及HNRNPU和MBD 5基因在中国儿童IS。我们的研究也支持婴儿痉挛症的分子机制在不同种族背景中是保守的。
Infantile spasms (IS) is a specific type of epileptic encephalopathy associated with severe developmental disabilities. Genetic factors are strongly implicated in IS, however, the exact genetic defects remain unknown in the majority of cases. Rare mutations in a single gene or in copy number variants (CNVs) have been implicated in IS of children in Western countries. The objective of this study was to dissect the role of copy number variations in Chinese children with infantile spasms. We used the Agilent Human Genome CGH microarray 180 K for genome-wide detection of CNVs. Real-time qPCR was used to validate the CNVs. We performed genomic and medical annotations for individual CNVs to determine the pathogenicity of CNVs related to IS. We report herein the first genome-wide CNV analysis in children with IS, detecting a total of 14 CNVs in a cohort of 47 Chinese children with IS. Four CNVs (4/47 = 8.5%) (1q21.1 gain; 1q44, 2q31.1, and 17p13 loss) are considered to be pathogenic. The CNV loss at 17p13.3 contains PAFAH1B1 (LIS1), a causative gene for lissencephaly. Although the CNVs at 1q21.1, 1q44, and 2q23.1 have been previously implicated in a wide spectrum of clinical features including autism spectrum disorders (ASD) and generalized seizure, our study is the first report identifying them in individuals with a primary diagnosis of IS. The CNV loss in the 1q44 region contains HNRNPU, a strong candidate gene recently suggested in IS by the whole exome sequencing of children with IS. The CNV loss at 2q23.1 includes MBD5, a methyl-DNA binding protein that is a causative gene of ASD and a candidate gene for epileptic encephalopathy. We also report a distinct clinical presentation of IS, microcephaly, intellectual disability, and absent hallux in a case with the 2q23.1 deletion. Our findings strongly support the role of CNVs in infantile spasms and expand the clinical spectrum associate with 2q23.1 deletion. In particular, our study implicates the HNRNPU and MBD5 genes in Chinese children with IS. Our study also supports that the molecular mechanisms of infantile spasms appear conserved among different ethnic backgrounds.
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影响因子：
30.8
作者：
Helbig I;Mefford HC;Sharp AJ;Guipponi M;Fichera M;Franke A;Muhle H;de Kovel C;Baker C;von Spiczak S;Kron KL;Steinich I;Kleefuss-Lie AA;Leu C;Gaus V;Schmitz B;Klein KM;Reif PS;Rosenow F;Weber Y;Lerche H;Zimprich F;Urak L;Fuchs K;Feucht M;Genton P;Thomas P;Visscher F;de Haan GJ;Møller RS;Hjalgrim H;Luciano D;Wittig M;Nothnagel M;Elger CE;Nürnberg P;Romano C;Malafosse A;Koeleman BP;Lindhout D;Stephani U;Schreiber S;Eichler EE;Sander T
通讯作者：
Sander T
影响因子：
3.7
作者：
Du Y;Liu B;Guo F;Xu G;Ding Y;Liu Y;Sun X;Xu G
通讯作者：
Xu G
MBD5的破坏有助于一系列精神病理学和神经发育异常。
影响因子：
11
作者：
Hodge JC;Mitchell E;Pillalamarri V;Toler TL;Bartel F;Kearney HM;Zou YS;Tan WH;Hanscom C;Kirmani S;Hanson RR;Skinner SA;Rogers RC;Everman DB;Boyd E;Tapp C;Mullegama SV;Keelean-Fuller D;Powell CM;Elsea SH;Morton CC;Gusella JF;DuPont B;Chaubey A;Lin AE;Talkowski ME
通讯作者：
Talkowski ME
影响因子：
8.8
作者：
Dolcetti, Alessia;Silversides, Candice K.;Bassett, Anne S.
通讯作者：
Bassett, Anne S.
影响因子：
64.8
作者：
通讯作者：
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