Clinical and laboratory observation
Phenotypic spectrum of CHARGE syndrome with CHD7 mutations

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CHD7 gene mutations were identified in 17 (71%) of 24 children clinically diagnosed to have CHARGE syndrome (C, coloboma of the iris or retina; H, heart defects; A, atresia of the choanae; R, retardation of growth and/or development; G, genital anomalies; and E, ear abnormalities). Colobomata, hearing loss, laryngomalacia, and vestibulo-cochlear defect were prevalent. Molecular testing for CHD7 enables an accurate diagnosis and provides health anticipatory guidance and genetic counseling to families with CHARGE syndrome.

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Methods

The subjects were recruited from a group of patients with CHARGE syndrome who were regularly followed at the authors’ institutions at the time of study (August 2004 to March 2005). A diagnosis of CHARGE syndrome was made according to the criteria defined by Blake et al.4 Blake’s major criteria are coloboma or microphthalmia, choanal atresia or stenosis, typical ear anomalies, and cranial nerve dysfunction. Choanal atresia was diagnosed by CT scan. The minor criteria are genital hypoplasia,

Results

We identified heterozygous CHD7 mutations in 17 (71%) of the 24 patients enrolled in the study: 7 frameshift mutations, 6 nonsense mutations, 3 splice-site mutations, and 1 intragenic deletion from exon 8 to 12 (Table). The clinical characteristics of the patients, including the presence or absence of the major and minor characteristics described by Blake et al,4 are listed in the Table and shown in the Figure. Only 3 patients had 4 of the major characteristics of CHARGE syndrome: 13 patients

Discussion

We have verified the validity of the existing diagnostic criteria for CHARGE syndrome. In view of the results of the mutation analysis, we wish to address two issues regarding the clinical diagnostic workup when a diagnosis of CHARGE syndrome is suspected. First, a detailed examination of the retina and the optic disc must be performed, even in the absence of iridal coloboma. Further, the absence of coloboma does not rule out the possible presence of a CHD7 mutation, since two of the patients

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Contract grant sponsors were The Ministry of Health, Labour, and Welfare of Japan. T.U. was supported by a research grant from Transgenomic, Inc, Omaha, Nebraska, whose machine was used to analyze the patients’ genomic DNA in the study.

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