Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation
Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation
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DOI：
10.1086/500273
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发表时间：
2006-02-01
影响因子：
9.8
通讯作者：
Belmont, JW
中科院分区：
文献类型：
--
作者：
Lalani, SR;Safiullah, AM;Belmont, JW
CHARGE综合征是一种公认的多发畸形综合征，具有独特的共识诊断标准。特征性相关异常包括眼缺损、后鼻孔闭锁、颅神经缺损、独特的外耳和内耳异常、听力丧失、心血管畸形、泌尿生殖系统异常和生长迟缓。最近，染色体结构域解旋酶DNA结合蛋白基因CHD 7的突变被报道是CHARGE综合征的主要原因。我们对110名接受CHARGE综合征临床诊断的个体进行了CHD 7基因测序，并在64名（58%）中检测到突变。突变分布在CHD 7的整个编码外显子和保守的剪接位点。在64个突变中，47个（73%）预测蛋白质的过早截短。这些包括无义突变和移码突变，最有可能导致单倍不足。表型上，突变阳性组更容易出现心血管畸形（突变阳性组59例中有54例，突变阴性组42例中有30例; P = 0.014），（突变阳性组62例中有55例，突变阴性组43例中有30例; P = .022）和面部不对称，通常由第七脑神经异常引起（突变阳性组56例中有36例，突变阴性组39例中有13例; P = .004）小鼠胚胎整体和切片原位杂交显示Chd 7在心脏流出道、视泡、面声前神经节复合体、脑、嗅窝、微阵列基因表达分析显示了基因表达差异的特征模式，将CHD 7突变的CHARGE综合征患者与对照组区分开来。我们的结论是，心血管畸形，缺损，面部不对称是常见的CHD 7突变引起的CHARGE综合征的结果。
CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 ( 58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 ( 73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations ( 54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P = .014), coloboma of the eye ( 55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P = .022) and facial asymmetry, often caused by seventh cranial nerve abnormalities ( 36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P = .004) Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facioacoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.