Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions

Vuorela, Pia E.; Ala‐Mello, Sirpa; Saloranta, Carola; Penttinen, Maila; Pöyhönen, Minna; Huoponen, Kirsi; Borozdin, Wiktor; Bausch, Birke; Botzenhart, Elke; Wilhelm, Christian; Kääriäinen, Helena; Kohlhase, Jürgen

doi:10.1097/gim.0b013e318156e68e

Cited by 44 publications

(39 citation statements)

References 20 publications

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“…There is a higher percentage of stop codons in our cohort than in the published literature (52.7% vs. 35.4%). Of 189 published mutations, there were 35.4% stop mutations, 33.3% frameshifts, 7%-15% splicing mutations, 6%-13% missense mutations, and 3% large deletion/duplications (Vissers et al, 2004;Felix et al, 2006;Jongmans et al, 2006;Lalani et al, 2006;Sanlaville et al, 2006;Aramaki et al, 2007;Vuorela et al, 2007;Asakura et al, 2008;Bergman et al, 2008;Gennery et al, 2008;Wincent et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…DNA sequencing detects CHD7 mutations in *58%-64% of patients clinically diagnosed with CHARGE syndrome (Vissers et al, 2004;Jongmans et al, 2006;Lalani et al, 2006). Of the CHD7 mutations reported thus far, *70% are nonsense or frameshift, 6%-13% are missense, and 7%-15% are splice site mutations (Vissers et al, 2004;Felix et al, 2006;Jongmans et al, 2006;Lalani et al, 2006;Sanlaville et al, 2006;Aramaki et al, 2007;Vuorela et al, 2007;Asakura et al, 2008;Bergman et al, 2008;Gennery et al, 2008;Wincent et al, 2008). Partial and whole gene deletions or duplications are rare, accounting for 3%-4% of pathogenic CHD7 mutations (Aramaki et al, 2006;Vuorela et al, 2007;Bergman et al, 2008;Wincent et al, 2008).…”

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confidence: 99%

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Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory

Bartels

Scacheri²,

White³

et al. 2010

Genetic Testing and Molecular Biomarkers

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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 ¼ 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 ¼ 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 ¼ 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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory

Bartels

Scacheri²,

White³

et al. 2010

Genetic Testing and Molecular Biomarkers

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“…Typical of most sequencing studies, deepintronic and regulatory-regions, deletions, and rearrangements were not evaluated. However, in previous studies of CHD7 mutations, no such deletions have been found (6,26). While IGD subjects underwent Sanger sequencing, control CHD7 alleles were obtained from whole-exome seqencing data from the NHLBI ESP Exome Variant Server and, hence, potentially could be subject to platform-specific biases in variant ascertainment.…”

Section: Discussionmentioning

confidence: 99%

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Balasubramanian¹,

Choi

Francescatto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.CHD7 | Kallmann syndrome | idiopathic hypogonadotropic hypogondism | CHARGE syndrome | missense mutations

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“…In this article, we give an overview of all CHD7 missense variants reported in the literature before 15 June 2011 [Asakura et al, 2008;Bartels et al, 2010;Bergman et al, 2011a, b;Dauber et al, 2010;De Arriba Munoz et al, 2011;Delahaye et al, 2007;Felix et al, 2006;Feret et al, 2010;Fujita et al, 2009;Gao et al, 2007;Holak et al, 2008;Jongmans et al, 2006Jongmans et al, , 2008Jongmans et al, , 2009Kim et al, 2008;Lalani et al, 2006;Pauli et al, 2012;Vissers et al, 2004;Vuorela et al, 2007;Wessels et al, 2010;Wincent et al, 2008] and the variants that were reported in the NCBI Single Nucleotide Polymorphism database (http://www.ncbi.nlm.nih.gov/SNP, dbSNP build 132) with frequency data (n = 104, Supp. Table S1).…”

Section: Inclusion Of Chd7 Missense Variantsmentioning

confidence: 99%

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

et al. 2012

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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.

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Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions

Cited by 44 publications

References 20 publications

Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory

Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

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