<i>CHD7</i> mutations causing CHARGE syndrome are predominantly of paternal origin

Pauli, Silke; Velsen, Nina von; Burfeind, Peter; Steckel, M; Mänz, Johanna; Buchholz, Annick; Borozdin, Wiktor; Kohlhase, Jürgen

doi:10.1111/j.1399-0004.2011.01701.x

Cited by 20 publications

(14 citation statements)

References 38 publications

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“…4 and Table 1). These findings contrast previously reported CHARGEcausing variants that are typically de novo and show a preference for paternal inheritance (23). Segregation analysis also showed that the discovered CHD7 alleles are not sufficient to explain the observed phenotypes (Fig.…”

Section: Deleterious Chd7 Missense Variants Cause Both Ks and Nigd Wicontrasting

confidence: 92%

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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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Section: Deleterious Chd7 Missense Variants Cause Both Ks and Nigd Wicontrasting

confidence: 92%

“…To date, only a few cases of parent-to-child transmission have been reported in CHARGE pedigrees with CHD7 mutation (23,25). In addition, over 80% of CHARGE-causing CHD7 mutations are null alleles (5,6).…”

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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“…In contrast to the de novo and paternal origin of mutations associated with severe CHARGE (Pauli et al 2012), the vast majority of IHH-associated CHD7 variants is inherited, often from unaffected parents, and exhibit no apparent parent of origin bias (Balasubramanian et al 2014). In addition, in reports where segregation analysis of CHD7 missense alleles is available, there is considerable incomplete penetrance for the IHH phenotype in those harboring CHD7 missense mutations (Marcos et al 2014; Balasubramanian et al 2014).…”

Section: Missense Allelic Variants In Chd7 Can Cause Ihh In the Absenmentioning

confidence: 99%

Reproductive endocrine phenotypes relating to CHD7 mutations in humans

Balasubramanian

Crowley

2017

American J of Med Genetics Pt C

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Mutations in the gene CHD7 cause CHARGE syndrome, a rare multi-organ syndromic disorder. Gonadal defects are common in individuals with CHARGE syndrome (seen in ~60–80% of cases) and represent the letter “G” in the CHARGE syndrome acronym. The gonadal defect in CHARGE syndrome results from congenital deficiency of the hypothalamic hormone Gonadotropin-releasing hormone (GnRH), which manifests clinically as pubertal failure and infertility, and biochemically as hypogonadotropic hypogonadism (low sex steroid hormone levels with inappropriately normal or low gonadotropin levels). In addition to the gonadal endocrine abnormalities, in a small minority of individuals with CHARGE, additional endocrine defects including growth hormone deficiency, multiple pituitary hormone deficits and primary hypothyroidism may also be seen. CHD7 mutations disrupt the targeting of olfactory axons and the migration of GnRH-synthesizing neurons during embryonic development, resulting in congenital idiopathic hypogonadotropic hypogonadism (IHH) and anosmia (or hyposmia), two features that define human Kallmann syndrome. Since Kallmann syndrome is as one of its constituent phenotypes in individuals with CHARGE, recent studies have investigated the role of CHD7 mutations in individuals with IHH and established that deleterious missense mutations in CHD7 are associated with Kallmann syndrome as well as normosmic form of IHH. These missense mutations affect the ATPase and nucleosome remodeling activities of the CHD7 protein. These observations suggest that CHD7 protein function is critical for the ontogeny of GnRH neurons and neuroendocrine regulation of GnRH secretion.

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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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CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin

Cited by 20 publications

References 38 publications

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Reproductive endocrine phenotypes relating to CHD7 mutations in humans

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

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