Mutations in the CHD7 gene: the experience of a commercial laboratory - PubMed (original) (raw)

Mutations in the CHD7 gene: the experience of a commercial laboratory

Cynthia F Bartels et al. Genet Test Mol Biomarkers. 2010 Dec.

Abstract

CHARGE syndrome is an autosomal dominant multisystem disorder caused by mutation in the CHD7 gene, encoding chromodomain helicase DNA-binding protein 7. Molecular diagnostic testing for CHD7 mutation has been available in a clinical setting since 2005. We report here the results from the first 642 unrelated proband samples submitted for testing. Thirty-two percent (n = 203) of patient samples had a heterozygous pathogenic variant identified. The lower mutation rate than that published for well-characterized clinical samples is likely due to referral bias, as samples submitted for clinical testing may be for "rule-out" diagnoses, rather than solely to confirm clinical suspicion. We identified 159 unique pathogenic mutations, and of these, 134 mutations were each seen in a single individual and 25 mutations were found in two to five individuals (n =69). Of the 203 mutations, only 9 were missense, with 107 nonsense, 69 frameshift, and 15 splice-site mutations likely leading to haploinsufficiency at the cellular level. An additional 72 variations identified in the 642 tested samples (11%) were considered to have unknown clinical significance. Copy number changes (deletion/duplication of the entire gene or one/several exons) were found to account for a very small number of cases (n = 3). This cohort represents the largest CHARGE syndrome sample size to date and is intended to serve as a resource for clinicians, genetic counselors, researchers, and other diagnostic laboratories.

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Figures

FIG. 1.

FIG. 1.

The CHD7 gene (top) and protein (bottom). Colored circles above exons 2–38 depict the location of 200 CHARGE-causing mutations. Overlapping circles indicate identical mutations. Protein domains are labeled and lines indicate where each protein domain is encoded on the gene. All DNA mutations that introduced stop codons or frameshifts were considered disease causing, as were mutations of the canonical splice donor–acceptor pair (GT-AG). Missense changes or other putative splicing changes were not considered disease causing unless the change was a de novo mutation not found in either parent or if it was reported in the literature as a de novo mutation.

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References

    1. Antonarakis SE. Krawczak M. Cooper DN. Disease-causing mutations in the human genome. Eur J Pediatr. 2000;159(Suppl 3):S173–S178. - PubMed
    1. Aramaki M. Kimura T. Udaka T, et al. Embryonic expression profile of chicken CHD7, the ortholog of the causative gene for CHARGE syndrome. Birth Defects Res A Clin Mol Teratol. 2007;79:50–57. - PubMed
    1. Aramaki M. Udaka T. Kosaki R, et al. Phenotypic spectrum of CHARGE syndrome with CHD7 mutations. J Pediatr. 2006;148:410–414. - PubMed
    1. Asakura Y. Toyota Y. Muroya K, et al. Endocrine and radiological studies in patients with molecularly confirmed CHARGE syndrome. J Clin Endocrinol Metab. 2008;93:920–924. - PubMed
    1. Bergman JE. de Wijs I. Jongmans MC, et al. Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome. Eur J Med Genet. 2008;51:417–425. - PubMed

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