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Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation.

Abstract：

: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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Lalani SR,Safiullah AM,Fernbach SD,Harutyunyan KG,Thaller C,Peterson LE,McPherson JD,Gibbs RA,White LD,Hefner M,Davenport SL,Graham JM,Bacino CA,Glass NL,Towbin JA,Craigen WJ,Neish SR,Lin AE,Belmont JW

doi

10.1086/500273

subject

Has Abstract

pub_date

2006-02-01 00:00:00

pages

303-14

issue

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(07)62361-1

journal_volume

pub_type

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Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation.