| Summary: | CHARGE association, or syndrome as it is now known, is a condition where a number of congenital malformations are non-randomly associated in a recognizable pattern. There are two sets of diagnostic criteria for CHARGE syndrome which are in common usage at present (Blake et al., 1998; Verloes, 2005). The etiology of CHARGE syndrome was unknown. We identified twin girls with CHARGE syndrome and a de novo apparently balanced chromosome translocation 46,XX,t(8;13)(q11.2;q22). By mapping the chromosome translocation breakpoints we found that the gene chromodomain-helicase-DNA-binding protein 7 (CHD7) located at 8q12 was disrupted in these girls. CHD7 has a genomic length of 188kb with 9000 coding bases over 37 exons. It has a putative function as a transcription factor which makes it a good candidate gene for a condition which affects multiple body systems. Concurrently with this study Vissers et al (2004) identified CHD7 as a cause of CHARGE syndrome. They found two individuals with CHARGE syndrome with overlapping microdeletions detected by array CGH. By sequencing the 9 genes in this region in a cohort of 17 cases they identified a mutation in CHD7 in 10 cases. We ascertained a cohort of 45 patients with a diagnosis of CHARGE syndrome or possible CHARGE syndrome by scrutinizing the clinical genetics databases in Glasgow and Sheffield. Part of the cohort was accessed by receipt of samples from clinical genetics departments elsewhere in the U.K. and in Lisbon. Clinical information was acquired on this cohort either by examination and review of the clinical notes by the author or by completion of a proforma by the referring clinician. Sequencing in this cohort of 45 patients was successful in 43 individuals. We identified 28 mutations; 16 nonsense, 10 frameshift and 2 splice site mutations. 20 of the mutations were novel, 8 had been reported in other studies. The mutations were found throughout the gene with no particular hotspots. No genotype/phenotype correlations were found either in relationship to the position of the mutation within the gene or with regards to the type of mutation. I have analyzed the phenotype in our cohort and compared it with the cases of CHARGE association reported prior to the availability of mutation analysis. I have also compared the phenotype in our mutation positive cases with those reported in other studies which were mutation-positive. We report two individuals with rare findings in CHARGE syndrome; one with a palsy of the twelfth cranial nerve reported anecdotally only once before (Blake et al., 2008), and another child with a limb reduction defect which has been reported in five other cases (Aramaki et al., 2006; Asamoah et al.,2004; Van de Laar et al., 2007). Our notes review ascertained an incidence of CHARGE syndrome of 1/10,000.
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