De novo Splice Site Mutation of the CHD7 Gene in a Chinese Patient with Typical CHARGE Syndrome
De novo Splice Site Mutation of the CHD7 Gene in a Chinese Patient with Typical CHARGE Syndrome
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中国典型 CHARGE 综合征患者 CHD7 基因的从头剪接位点突变
DOI：
10.1159/000520376
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发表时间：
2022-01-25
影响因子：
1.3
通讯作者：
Zha，Dingjun
中科院分区：
文献类型：
--
作者：
Wang，Shujuan;Lin，Ying;Zha，Dingjun
CHARGE综合征（CS，OMIM 214800）是一种罕见的遗传性疾病，以多种先天性畸形为特征，包括缺损、心脏缺陷、软骨闭锁、发育迟缓、生殖器畸形和耳畸形/耳聋。该综合征主要是由杂合变异的chromodomain解旋酶DNA结合蛋白7（CHD 7）基因编码的CHD 7蛋白，参与ATP依赖性重塑的chromatin.MethodsIn这项研究中，下一代测序靶向面板被用来检测从头变异c。3523-2A> G在患有严重CS、先天性心脏病、脉络膜左侧缺损、隐睾症和先天性耳聋的患者中的CHD 7基因中。桑格测序证实了该变异，并通过患者家族中的短串联重复序列分析阐明其为新发变异。我们通过Minigene检测分析了一个变异体的作用，以评估该变异体的致病性。3523-2A> G突变体激活了一个隐蔽的剪接位点，导致CHD 7基因外显子15缺失172个碱基，导致CHD 7蛋白（p.V1175Afs * 11）提前截短。3523-2A> G变异在CHD 7中的表达，提供了进一步证实其与CS相关的证据。
IntroductionCHARGE syndrome (CS, OMIM 214800) is a rare genetic disease characterized by multiple congenital abnormalities, including coloboma, heart defect, atresia of the choanae, retardation of development, genital anomalies, and ear anomalies/deafness. The syndrome is mainly caused by a heterozygous variant in the chromodomain helicase DNA-binding protein 7 (CHD7) gene that encodes the CHD7 protein, involved in the ATP-dependent remodeling of chromatin.MethodsIn this study, the next-generation sequencing targeted panel was used to detect a de novo variant c. 3523-2A> G in the CHD7 gene in a patient with severe CS, congenital heart disease, left coloboma of the choroid, cryptorchidism, and congenital deafness. The Sanger sequencing confirmed the variant and clarified it as de novo variant by short tandem repeat analysis in the patient family. We analyzed the effect of a variant by Minigene assay to evaluate the pathogenicity of the variant.ResultsIn summary, cDNA analysis confirmed that c. 3523-2A> G variant activates a cryptic splice site, resulting in 172 base pair missing in exon 15, leading to the premature truncation of the CHD7 protein (p. V1175Afs* 11).ConclusionThe present study functionally characterized the novel c. 3523-2A> G variant in CHD7, providing further confirmatory evidence that it is associated with CS.