TY - JOUR
T1 - Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation
AU - Lalani, Seema R.
AU - Safiullah, Arsalan M.
AU - Fernbach, Susan D.
AU - Harutyunyan, Karine C.
AU - Thaller, Christina
AU - Peterson, Leif E.
AU - McPherson, John D.
AU - Gibbs, Richard A.
AU - White, Lisa D.
AU - Hefner, Margaret
AU - Davenport, Sandra L.H.
AU - Graham, John M.
AU - Bacino, Carlos A.
AU - Glass, Nancy L.
AU - Towbin, Jeffrey A.
AU - Craigen, William J.
AU - Neish, Steven R.
AU - Lin, Angela E.
AU - Belmont, John W.
N1 - Funding Information:
We are deeply grateful to all the individuals with CHARGE syndrome and their families who continue to participate in this study. We also thank Benjamin B. Roa for assisting in this study. This work was funded by the Doris Duke Clinical Scientist Developmental Award (to S.R.L.) and National Institutes of Health (NIH) grant RO1HD39056 (to J.W.B.). J.M.G. was supported by SHARE's Child Disability Center and the Steven Spielberg Pediatric Research Center. In addition, this work was supported by the University of California–Los Angeles Intercampus NIH/National Institute of General Medical Sciences Medical Genetics Training Program grant GM08243 and NIH/National Institute of Child Health and Human Development grant HD22657 from the U.S. Department of Health and Human Services, Public Health Service.
PY - 2006/2
Y1 - 2006/2
N2 - CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P = .014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P = .022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P = .004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.
AB - CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P = .014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P = .022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P = .004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.
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U2 - 10.1086/500273
DO - 10.1086/500273
M3 - Article
C2 - 16400610
AN - SCOPUS:31544463054
SN - 0002-9297
VL - 78
SP - 303
EP - 314
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -