Mutations in the CHD7 gene, a new member of the chromodomain gene family, cause CHARGE syndrome. CHARGE syndrome is a nonrandom pattern of congenital anomalies, including choanal atresia, heart, inner ear, and retinal malformations. It has an incidence of 1 in 12,000. Most cases are sporadic, but some familial cases and high concordance in monozygotic twins suggest a genetic component. Previous studies failed to identify a specific locus. Using array CGH, researchers identified a 2.3-Mb de novo microdeletion on 8q12 in two individuals with CHARGE syndrome. Sequence analysis of genes in this region revealed mutations in CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for most cases. The CHD7 gene, which is 188 kb long and consists of 38 exons, was found to have seven stop-codon mutations, two missense mutations, and one intron-exon boundary mutation. These mutations are scattered throughout the gene, with two de novo missense mutations predicted to cause amino acid substitutions. The study also identified two distinct microdeletions in an individual with a balanced translocation. The deletion of CHD7 is likely responsible for most cases of CHARGE syndrome, as haploinsufficiency of this gene may account for the condition. The study highlights the importance of high-resolution genome-wide screening using array CGH to identify underlying genes in sporadic malformation syndromes. The findings suggest that CHARGE syndrome may have a genetically heterogeneous etiology, with different genomic abnormalities in affected individuals. The study also notes that CHARGE syndrome may overlap with DiGeorge syndrome in some cases. The identification of mutations in CHD7 provides a genetic basis for understanding the pathogenesis of CHARGE syndrome.Mutations in the CHD7 gene, a new member of the chromodomain gene family, cause CHARGE syndrome. CHARGE syndrome is a nonrandom pattern of congenital anomalies, including choanal atresia, heart, inner ear, and retinal malformations. It has an incidence of 1 in 12,000. Most cases are sporadic, but some familial cases and high concordance in monozygotic twins suggest a genetic component. Previous studies failed to identify a specific locus. Using array CGH, researchers identified a 2.3-Mb de novo microdeletion on 8q12 in two individuals with CHARGE syndrome. Sequence analysis of genes in this region revealed mutations in CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for most cases. The CHD7 gene, which is 188 kb long and consists of 38 exons, was found to have seven stop-codon mutations, two missense mutations, and one intron-exon boundary mutation. These mutations are scattered throughout the gene, with two de novo missense mutations predicted to cause amino acid substitutions. The study also identified two distinct microdeletions in an individual with a balanced translocation. The deletion of CHD7 is likely responsible for most cases of CHARGE syndrome, as haploinsufficiency of this gene may account for the condition. The study highlights the importance of high-resolution genome-wide screening using array CGH to identify underlying genes in sporadic malformation syndromes. The findings suggest that CHARGE syndrome may have a genetically heterogeneous etiology, with different genomic abnormalities in affected individuals. The study also notes that CHARGE syndrome may overlap with DiGeorge syndrome in some cases. The identification of mutations in CHD7 provides a genetic basis for understanding the pathogenesis of CHARGE syndrome.