Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE syndrome and CHARGE-like syndrome

Department of Genetics, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
European Journal of Medical Genetics (Impact Factor: 1.47). 05/2008; 51(5):417-25. DOI: 10.1016/j.ejmg.2008.03.003
Source: PubMed


CHARGE syndrome is a multiple congenital anomaly syndrome caused by mutations in the CHD7 gene. Mutations in this gene are found in 60-70% of patients suspected of having CHARGE syndrome. However, if only typical CHARGE patients are taken into account, mutations in the CHD7 gene are found in over 90% of cases. The remaining 10% might be caused by hitherto undetected alterations of the CHD7 gene, including whole exon duplications and deletions that are missed by the currently used diagnostic procedures. Therefore we looked for these kinds of alterations by multiplex ligation-dependent probe amplification in 54 patients suspected of having CHARGE syndrome without a CHD7 mutation. In one patient a partial deletion of the CHD7 gene (exons 13-38) was identified, while in the other patients no abnormalities were found. The frequency of exon deletions in our cohort was 1.9% (1/54) and 5.6% (1/18) in all patients and in typical CHARGE patients, respectively. We conclude that exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome.

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Available from: Conny van Ravenswaaij-Arts, Oct 09, 2015
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    • "t al. [2008]); wg = whole gene; 0 = not mentioned in the online database. a Gennery et al., 2008. b Writzl et al., 2007. c Inoue et al., 2010. d Wincent et al., 2008. e Kaliakatsos et al., 2010. f Vuorela et al., 2007. g Vuorela et al., 2008. h Van de Laar et al., 2007. i Jongmans et al., 2006. j Hoover-Fong et al., 2009. k Vissers et al., 2004. l Bergman et al., 2011a. m Sanka et al., 2007. n Randall et al., 2009. o Chopra et al., 2008. * Atresia or stenosis of choanae. ** Only if necessitating tube feeding."
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    ABSTRACT: CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.
    Molecular syndromology 06/2013; 4(5):235-45. DOI:10.1159/000351127
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    • "CHD7 analysis was performed as previously described [Jongmans et al., 2006] and multiplex ligation-dependent probe amplification (MLPA) was performed if CHD7 sequence analysis did not identify a mutation [Bergman et al., 2008]. The GenBank accession number NM_017780.2 was used as reference sequence for the CHD7 gene. "
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    ABSTRACT: CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo- and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5' and 3' regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations.
    Human Mutation 08/2012; 33(8):1251-60. DOI:10.1002/humu.22106 · 5.14 Impact Factor
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    • "Seventeen families with multiple affected members due to a segregating CHD7 mutation have been reported to date [Bergman et al., 2011b; Delahaye et al., 2007; Jongmans et al., 2006, 2008; Lalani et al., 2006; Pauli et al., 2009; Vuorela et al., 2008; Wincent et al., 2008]. In addition, we identified a presumed pathogenic missense mutation (c.6221T>C; p.Leu2074Pro) in two sisters with KS, whose clinical features were previously reported by Levy and Knudtzon (1993). "
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    ABSTRACT: CHD7 is a member of the chromodomain helicase DNA-binding (CHD) protein family that plays a role in transcription regulation by chromatin remodeling. Loss-of-function mutations in CHD7 are known to cause CHARGE syndrome, an autosomal-dominant malformation syndrome in which several organ systems, for example, the central nervous system, eye, ear, nose, and mediastinal organs, are variably involved. In this article, we review all the currently described CHD7 variants, including 183 new pathogenic mutations found by our laboratories. In total, we compiled 528 different pathogenic CHD7 alterations from 508 previously published patients with CHARGE syndrome and 294 unpublished patients analyzed by our laboratories. The mutations are equally distributed along the coding region of CHD7 and most are nonsense or frameshift mutations. Most mutations are unique, but we identified 94 recurrent mutations, predominantly arginine to stop codon mutations. We built a locus-specific database listing all the variants that is easily accessible at In addition, we summarize the latest data on CHD7 expression studies, animal models, and functional studies, and we discuss the latest clinical insights into CHARGE syndrome.
    Human Mutation 08/2012; 33(8):1149-60. DOI:10.1002/humu.22086 · 5.14 Impact Factor
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