Molecular Genetics of CHARGE Syndrome


Coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital abnormalities and ear abnormalities and deafness (CHARGE) syndrome is a highly variable, multiple congenital anomaly syndrome with an estimated prevalence of 1 in 17 000. The main features are hypoplasia of the semicircular canals, coloboma, choanal atresia, heart defects, hypogonadotropic hypogonadism, ear malformations, deafness, cranial nerve dysfunction and cleft/lip palate. The phenotype shows a remarkable variability that cannot be explained by different genotypes. In most patients a de novo autosomal dominant loss‐of‐function mutation of chromodomain helicase deoxyribonucleic acid (DNA)‐binding gene 7 (CHD7) is found. The CHD protein family plays a role in transcription regulation by chromatin remodelling. Expression studies as well as studies in stem cells, neural crest cells and animal models have revealed that CHD7 has a tissue‐ and embryonic stage‐specific function in enhancer‐mediated transcription. The broad phenotypic spectrum involving many organ systems that is seen in CHD7 haploinsufficiency can be explained by cell type‐specific binding sites, protein complexes and target genes of CHD7.

Key Concepts:

  • CHARGE syndrome is a multiple congenital anomaly syndrome with a highly variable and broad clinical spectrum.

  • CHARGE syndrome shows remarkable clinical overlap with other multiple congenital anomaly syndromes. In contrast, CHD7 mutations do not cause nonsyndromic congenital defects.

  • CHD7 is the main causal gene in CHARGE syndrome and codes for a chromodomain protein.

  • Chromodomain proteins are important during embryonic development.

  • CHD7 has a function in enhancer‐mediated transcription.

  • Both the expression of CHD7 and its binding sites to genomic enhancer regions are cell type‐ and embryonic stage‐dependent.

  • CHD7 haploinsufficiency alters transcription of tissue‐specific target genes that are normally regulated by CHD7 or complexes in which CHD7 is involved.

  • CHD7 plays an important role in neural crest cells and the interaction of the neural crest with other tissues.

  • Investigation of overlapping phenotypes and converging molecular pathways gives insight into the pathogenesis.

Keywords: CHD7; CHARGE syndrome; enhancer‐mediated transcription; chromodomain protein; phenotypic variability; mutation spectrum; 22q11.2 deletion syndrome; Kallmann syndrome

Figure 1.

Clinical features of CHARGE syndrome. The acronym of CHARGE syndrome represents its major features: Coloboma ((a) iris coloboma of the right eye), Heart defect, Atresia of the choanae ((b) unilateral choanal atresia), Retardation of growth or development, Genital hypoplasia ((c) micropenis) and Ear abnormalities and deafness (d). Other frequently occurring features are agenesis of the semicircular canals ((e) dashed arrow points towards the basal curve of the cochlea, full arrow points towards the place where semicircular canals normally are be visible, middle ear cavity (MC)), cleft lip and/or palate (f) and facial palsy (g). Reproduced with permission from patients or their legal representatives.

Figure 2.

Overview of reported CHD7 mutations. All mutations reported thus far aligned along a schematic representation of the CHD7 protein (e): splice site (a), missense (b), frameshift (c) and nonsense mutations (d). The mutations are spread over the CHD7 gene, but missense mutations occur only in the middle of the gene. For explanation of the domains in the protein see Figure . Adapted from Janssen et al. .

Figure 3.

The CHD7 gene, complementary DNA (cDNA) and protein. Overview of the CHD7 gene with its 38 exons and introns (bottom). The size of the exons and introns are drawn to scale. The cDNA consists of 37 exons: the first exon and also part of genomic exon 2 and 38 are noncoding (middle). The CHD7 protein consists of 2997 amino acids and has several conserved domains which are drawn to scale (top). Chromatin organisation modifier, Chromodomain; SNF2 family N‐terminal domain, SNF2_N; DEAD‐like helicases superfamily including an ATP‐binding domain, DEXDc; Helicase superfamily C‐terminal domain, Helicase C; switching‐defective protein 3, adaptor 2, nuclear receptor co‐repressor, transcription factor IIIB domain, SANT domain; Brahma and Kismet domain, BRK domain. Reproduced with permission from Janssen et al., .



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Further Reading

Blake KD and Prasad C (2006) CHARGE syndrome. Orphanet Journal of Rare Diseases 1(1): 34.

Layman WS, Hurd EA and Martin DM (2010) Chromodomain proteins in development: lessons from CHARGE syndrome. Clinical Genetics 78(1): 11–20.

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van Ravenswaaij‐Arts, Conny M A, and Hoefsloot, Lies H(Nov 2012) Molecular Genetics of CHARGE Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024289]