Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2006; 78(2):303-14. DOI: 10.1086/500273
Source: PubMed

ABSTRACT 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, facio-acoustic 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.

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Available from: Leif Peterson, Sep 26, 2015
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    • "The conserved role of DNA-binding domain in CHD proteins suggests the same function of this domain in CHD7. Although the function of BRK domains is currently unknown, it is interesting to note that mutation that introduces a stop codon in the middle of the second BRK domain causes CHARGE syndrome, suggesting the importance of this region (Lalani et al., 2006). Feng et al. reported that CHD7 stimulates the expression of Sox4 and Sox11 genes in neuron stem cells via remodeling their promoters to an open chromatin state, thus regulating stem cell differentiation (Feng et al., 2013). "
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    ABSTRACT: In Genetics Out-patient Department of Shanghai Children's Medical Center, we consulted a 3-year-old boy with multiple anomaly syndrome (congenital heart disease, cryptorchidism, congenital deafness, mental retardation, exophthalmos, laryngeal cartilage dysplasia and high arched palate). We ruled out the possibility of multiple deformities caused by genomic imbalances. The patient was then clinically considered to have CHARGE syndrome, an autosomal dominant multi-system disorder involving defects in multiple organs, and CHD7 is the only known gene associated with the syndrome. Sequencing analysis of CHD7 of the proband identified a de novo heterogeneous mutation (c.2916_2917del, p.Gln972HisfsX22), a two-nucleotide deletion causing reading frame shift and resulting in a truncated CHD7 protein. Computational structure analysis suggests that the truncated protein only contains the chromodomains of CHD7, but lacks the SWI2/SNF2-like ATPase/helicase domain and the DNA binding domain, which are indispensable for the proper function of the protein, especially on chromatin remodeling. The patient then received follow up treatment in different clinical departments in a long period. To our best knowledge, this is the first CHARGE syndrome in Chinese patients diagnosed by gene analysis. In summary, the clinical symptoms and the description of treatment in the present case, combined with genetic test and functional prediction of CHD7, are helpful for further understanding and genetic counseling of the CHARGE syndrome.
    Meta Gene 12/2014; 2:469–478. DOI:10.1016/j.mgene.2014.06.002
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    • "Additionally, rare cases of non-syndromic coloboma have also been identified in patients with recessive mutations of VSX2 (formerly CHX10; OMIM 142993) (23) and ABCB6 (OMIM 605452) (24) more frequently associated with microphthalmia, dominant mutations of PAX6 (OMIM 607108) generally associated with a range of ocular defects including aniridia, and MAF (OMIM 610210) (cataract and anterior segment dysgenesis) (23–26). The most commonly identified genetic causes of isolated coloboma, without microphthalmia, are CHD7 (OMIM 608892) mutations associated with CHARGE syndrome (OMIM 214800) and PAX2 mutations, which cause renal-coloboma syndrome (OMIM 167409) (12,27,28). However, in the majority of cases, the genetic contribution to ocular coloboma phenotypes remains to be determined (9,13,14,16,20). "
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    ABSTRACT: Ocular coloboma is a congenital defect resulting from failure of normal closure of the optic fissure during embryonic eye development. This birth defect causes childhood blindness worldwide, yet the genetic aetiology is poorly understood. Here we identified a novel homozygous mutation in the SALL2 gene in members of a consanguineous family affected with non-syndromic ocular coloboma variably affecting the iris and retina. This mutation, c.85G>T, introduces a premature termination codon (p.Glu29*) predicted to truncate the SALL2 protein so that it lacks three clusters of zinc finger motifs that are essential for DNA binding activity. This discovery identifies SALL2 as the third member of the Drosophila homeotic Spalt-like family of developmental transcription factor genes implicated in human disease. SALL2 is expressed in the developing human retina at the time of, and subsequent to, optic fissure closure. Analysis of Sall2-deficient mouse embryos revealed delayed apposition of the optic fissure margins and the persistence of an anterior retinal coloboma phenotype after birth. Sall2-deficient embryos displayed correct posterior closure toward the optic nerve head, and upon contact of the fissure margins, dissolution of the basal lamina occurred and PAX2, known to be critical for this process, was expressed normally. Anterior closure was disrupted with the fissure margins failing to meet, or in some cases misaligning leading to a retinal lesion. These observations demonstrate, for the first time, a role for SALL2 in eye morphogenesis and that loss-of-function of the gene causes ocular coloboma in humans and mice.
    Human Molecular Genetics 01/2014; 23(10). DOI:10.1093/hmg/ddt643 · 6.39 Impact Factor
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    • "Loss of Chd2 in mice causes embryonic lethality (Marfella et al., 2006a) and conditional inactivation of CHD4 in hematopoietic cells impairs their differentiation and development (Williams et al., 2004). Haploinsufficient mutations of CHD7 are observed in 60-80% of cases of CHARGE syndrome (Janssen et al., 2012; Lalani et al., 2006; Layman et al., 2010; Zentner et al., 2010), a severe developmental disorder in humans characterized by coloboma of the eye, heart defects, atresia of the choanae, retardation of growth, and genital and ear abnormalities (Pagon et al., 1981). Chd7+/- mice recapitulate some of the human symptoms, and Chd7-/- mice are embryonic lethal (E10.5) "
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    ABSTRACT: Control of chromatin structure is crucial for multicellular development and regulation of cell differentiation. The CHD (chromodomain-helicase-DNA binding) protein family is one of the major ATP-dependent, chromatin remodeling factors that regulate nucleosome positioning and access of transcription factors and RNA polymerase to the eukaryotic genome. There are three mammalian CHD subfamilies and their impaired functions are associated with several human diseases. Here, we identify three CHD orthologs (ChdA, ChdB and ChdC) in Dictyostelium discoideum. These CHDs are expressed throughout development, but with unique patterns. Null mutants lacking each CHD have distinct phenotypes that reflect their expression patterns and suggest functional specificity. Accordingly, using genome-wide (RNA-seq) transcriptome profiling for each null strain, we show that the different CHDs regulate distinct gene sets during both growth and development. ChdC is an apparent ortholog of the mammalian Class III CHD group that is associated with the human CHARGE syndrome, and GO analyses of aberrant gene expression in chdC nulls suggest defects in both cell-autonomous and non-autonomous signaling, which have been confirmed through analyses of chdC nulls developed in pure populations or with low levels of wild-type cells. This study provides novel insight into the broad function of CHDs in the regulation development and disease, through chromatin-mediated changes in directed gene expression.
    Development 12/2013; 140(24):4926-36. DOI:10.1242/dev.099879 · 6.46 Impact Factor
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