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

TY - JOUR

T1 - A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

AU - Bergman, Jorieke E H

AU - Janssen, Nicole

AU - van der Sloot, Almer M

AU - de Walle, Hermien E K

AU - Schoots, Jeroen

AU - Rendtorff, Nanna D

AU - Tranebjaerg, Lisbeth

AU - Hoefsloot, Lies H

AU - van Ravenswaaij-Arts, Conny M A

AU - Hofstra, Robert M W

N1 - © 2012 Wiley Periodicals, Inc.

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

U2 - 10.1002/humu.22106

DO - 10.1002/humu.22106

M3 - Journal article

C2 - 22539353

SN - 1059-7794

VL - 33

SP - 1251

EP - 1260

JO - Human Mutation

JF - Human Mutation

IS - 8

ER -