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

Jorieke E. H. Bergman, Nicole Janssen, Almer M. van der Sloot, Hermien E. K. de Walle, Jeroen Schoots, Nanna D. Rendtorff, Lisbeth Tranebjaerg, Lies H. Hoefsloot, Conny M. A. van Ravenswaaij-Arts, Robert M. W. Hofstra*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

46 Citaten (Scopus)


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. Hum Mutat 33:12511260, 2012. (c) 2012 Wiley Periodicals, Inc.

Originele taal-2English
Pagina's (van-tot)1251-1260
Aantal pagina's10
TijdschriftHuman Mutation
Nummer van het tijdschrift8
StatusPublished - aug-2012

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