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

Department of Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, Texas, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2006; 78(2):303-14. DOI: 10.1086/500273
Source: PubMed


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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    • "CHARGE syndrome occurs in approximately 1 in every 10,000 newborns worldwide, and almost all cases of CHARGE syndrome occur sporadically (Bergman et al., 2011). The recurrence rate is approximately 1% among sib-pairs, monozygotic twins, and 2-generation families (Jongmans et al., 2006; Lalani et al., 2006; Delahaye et al., 2007; Jongmans et al., 2008; Vuorela et al., 2008; Wincent et al., 2008; Pauli et al., 2009; Bergman et al., 2011). Familial CHARGE syndrome follows an autosomal dominant inheritance with variable penetrance (Bergman et al., 2011). "
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    ABSTRACT: Most cases of CHARGE syndrome are sporadic and autosomal dominant. CHD7 is a major causative gene of CHARGE syndrome. In this study, we screened CHD7 in two Turkish patients who had CHARGE syndrome symptoms as coloboma, heart defect, choanal atresia, retarded growth and ear anomalies and found a novel splice-site mutation (c.2443-2A>G) and a previously known frameshift mutation (c.2504_2508delATCTT). We performed exon trapping analysis to determine the effect of the c.2443-2A>G mutation at the transcriptional level, and found that it caused a complete skip of exon 7 and splicing at a cryptic splice acceptor site. Our current study is the second study demonstrating an exon 7 deficit in CHD7. Results of previous studies suggest that the c.2443-2A>G mutation affects the formation of nasal tissues and the neural retina during early development, resulting in choanal atresia and coloboma, respectively. The findings of the present study will improve our understanding of the genetic causes of CHARGE syndrome.
    Full-text · Article · Nov 2015 · Gene
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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.
    Full-text · Article · Dec 2014 · Meta Gene
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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.
    Full-text · Article · Jan 2014 · Human Molecular Genetics
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