Clinical and genetic analysis of the CHD7 gene in Korean patients with CHARGE syndrome

To the Editor: The cardinal features of CHARGE syndrome (CS; OMIM 214800) include coloboma, heart malformations, choanal atresia, retardation of growth and/or development, genital anomalies, and ear anomalies (1). Other clinical findings such as dysmorphic features, rhombencephalic dysfunction, hypoplasia of the semicircular canals, and arhinencephaly have been added to the spectrum of CS (2). CS shows autosomal dominant inheritance and highly variable expression. CS is caused by mutations in the chromodomain helicase DNA-binding protein 7 gene (CHD7) on chromosome 8q12 (3). Mutations in CHD7 have been identified in approximately 60% of sporadic CS cases (4, 5). There is no apparent genotype–phenotype correlation, and extremely high variability of the phenotype is seen in carriers of the mutations. No CS patient nor genetically proven case of CS has been reported in Korea to date. As more than 400 patients have been reported in the worldwide literature, the incidence of CS may be underestimated in Korea (2). This study examined four unrelated patients who were diagnosed with CS. The clinical diagnostic criteria were those of Verloes (6). All patients had characteristic ears, congenital heart disease, and developmental delay suggestive of CS, with variable expression of other features (Table 1). Based on the clinical criteria, patients 1 and 3 were diagnosed as having typical CS. Patients 2 and 4, with no evidence of ocular coloboma or choanal atresia, were classified as those with atypical CS. All patients had congenital heart defects, with patent ductus arteriosus being the most common anomaly, followed by atrial septal defects. There was no choanal atresia or stenosis in any patient. All patients, except patient 1, had urogenital anomalies such as cryptorchidism, micropenis, and small ovary and uterus. All the patients had sensory neural hearing loss, resulting from anomalies of the middle ear, or aplasia of the semicircular canals. Direct sequencing analysis identified four heterozygous mutations in the CHD7 gene (Fig. 1). Patient 1 had a heterozygous mutation, a C to A transversion (c.2114C.A) in exon 4, that resulted in a nonsense change (p.Ser705X). A p.Arg1069X mutation, a C to T transition in exon 13 (c.3205C.T), was found in patient 2. Patient 3 had a heterozygous mutation, c.4601G. A in exon 20, that gave a nonsense change (p.Trp1534X). A heterozygous deletion mutation (c.1808_1811delACAA) in exon 3 predicted a frameshift (p.Asn603ThrfsX4) in patient 4. Recently, the CHD7 gene has been shown to be mutated in about 58% of CS cases in Americans and 64% of CS cases in the Dutch (4, 5). In this study, all patients had novel heterozygous mutations in the CHD7 gene. The four identified mutations scattered throughout the gene, showing no preferential domain aggregation or hot spot. Most of the identified mutations were nonsense mutations, consistent with a previous report (5). In the majority of affected individuals, haploinsufficiency of the CHD7 gene is likely the underlying basis of CS, based on the rare microdeletion cases involving the CHD7 gene as well as the stop mutations, which result in premature truncation of the protein (7). An in situ hybridization analysis showed a good correlation between specific CHD7 expression patterns and the developmental anomalies observed in CS (8). In particular, CHD7 is expressed in the semicircular canals, forebrain, olfactory bulbs and nerves, nasal epithelia, neural retina, and optic nerve sheath. Aplasia