Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE 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: 1.49). 05/2008; 51(5):417-25. DOI: 10.1016/j.ejmg.2008.03.003
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: -Loss-of-function mutations in CHD7 cause CHARGE syndrome, a variable combination of multiple congenital malformations including heart defects. Heart defects are reported in 66%-92% of patients with a CHD7 mutation, but most studies are small and do not provide a detailed classification of the defects. We present the first, detailed, descriptive study on the cardiac phenotype of 299 patients with a CHD7 mutation and discuss the role of CHD7 in cardiac development. METHODS AND RESULTS: -We have collected information on congenital heart defects in 299 patients with a pathogenic CHD7 mutation of whom 220 (74%) had a congenital heart defect. Detailed information on the heart defects was available for 202 of these patients. We classified the heart defects based on embryonic cardiac development and compared the distribution to 1,007 equally classified non-syndromic heart defects of patients registered by EUROCAT, a European Registry of Congenital Anomalies. Heart defects are highly variable in patients with CHD7 mutations, but atrioventricular septal defects (AVSD) and conotruncal heart defects are overrepresented. Gender did not have an effect on the presence of heart defects, but truncating CHD7 mutations resulted in a heart defect significantly more often than missense or splice-site mutations (chi-square, p<0.001). CONCLUSIONS: -CHD7 plays a very important role in cardiac development because we found a wide range of heart defects in 74% of a large cohort of patients with a CHD7 mutation. Conotruncal defects and AVSDs are overrepresented in patients with CHD7 mutations compared to patients with non-syndromic heart defects.
    Circulation Cardiovascular Genetics 05/2013; 6(3). DOI:10.1161/CIRCGENETICS.113.000054 · 5.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 5.05 Impact Factor


Available from
May 20, 2014