Multiple mutations in mouse Chd7 provide models for CHARGE syndrome

Bosman, Erika A.; Penn, Andrew C.; Ambrose, J. C.; Kettleborough, Ross; Stemple, Derek L.; Steel, Karen P.

doi:10.1093/hmg/ddi375

Cited by 201 publications

(253 citation statements)

References 61 publications

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“…Four benign variants (p.Ser103Thr, p.Met340Val, p.Gly522Val, and p.Phe2750Leu) were found in more than 15 index persons. Two of these variants (p.Ser103Thr and p.Gly522Val) were found in homozygous states and are, therefore, surely benign (mice with homozygous CHD7 mutations die in early embryogenesis [Bosman et al, 2005] and homozygous CHD7 mutations have never been found in a patient with CHARGE syndrome). The three most frequently occurring pathogenic missense mutations were each found in more than three index patients (p.Ile1028Val, p.Gln1214Arg, and p.Gly2108Arg).…”

Section: Classification 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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Section: Classification 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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“…Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism. 45 With the ENU mutagenesis program, Bosman et al 77 reported the identification of mutations in the Chd7 gene in nine of these mice mutant , including six nonsense and three splice-site mutations. These Wheels heterozygous mutant mice revealed a range of defects with reduced penetrance, such as truncations of the lateral semicircular canal, cleft palate, choanal atresia, septal defects of the heart, hemorrhages, prenatal death, vulva and clitoral defects and keratoconjunctivitis sicca that mimics human CHARGE syndrome.…”

Section: Prenatal Diagnosis and Fetal Pathologymentioning

confidence: 99%

CHARGE syndrome: an update

2007

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In association with CHARGE syndrome: an update CHARGE syndrome is a rare, usually sporadic autosomal dominant disorder due in 2/3 of cases to mutations within the CHD7 gene. The clinical definition has evolved with time. The 3C triad (ColobomaChoanal atresia-abnormal semicircular Canals), arhinencephaly and rhombencephalic dysfunctions are now considered the most important and constant clues to the diagnosis. We will discuss here recent aspects of the phenotypic delineation of CHARGE syndrome and highlight the role of CHD7 in its pathogeny. We review available data on its molecular pathology as well as cytogenetic and molecular evidences for genetic heterogeneity within CHARGE syndrome.

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“…CHD7 protein is mainly expressed in epithelial cells, olfactory epithelium, and eye, ear, and kidney tissues as well as the vascular system. 26 During the early embryonic stage, CHD7 protein is preferentially expressed in the undifferentiated neuroepithelium and mesenchyme of neural crest origin. 27 These facts closely correspond with the clinical manifestations of CHARGE syndrome.…”

Section: (ϫ35)mentioning

confidence: 99%

Abnormal Basiocciput Development in CHARGE Syndrome

Fujita¹,

Aida²,

Asakura³

et al. 2008

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:The causative gene of the common congenital malformation referred to as CHARGE syndrome is CHD7. Affected individuals often undergo head and neck imaging to assess abnormalities of the olfactory structures, hypothalamus-pituitary axis, and inner ear. We encountered a few children with severe hypoplasia of the basiocciput during a radiologic assessment of patients with CHARGE syndrome. To our knowledge, this anomaly has not been reported. Our purpose was to evaluate the incidence and severity of this anomaly in this syndrome.

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Multiple mutations in mouse Chd7 provide models for CHARGE syndrome

Cited by 201 publications

References 61 publications

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

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

CHARGE syndrome: an update

Abnormal Basiocciput Development in CHARGE Syndrome

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