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The theory must eventually pass the ultimate test, that is, molecular confirmation of the proposed mechanism. Several theories about the pathogenesis of CHARGE syndrome have been proposed, but none of these meet the three criteria stated above. In this study, the author proposes that CHARGE syndrome is due to a disruption of mesenchymal\u2013epithelial interaction (epithelial includes ectoderm and endoderm). The theory is tested against the major, minor, and occasional anomalies that are used to make the clinical diagnosis of CHARGE syndrome. Review of the known embryology of the organs and tissues involved in CHARGE syndrome confirms that mesenchymal\u2013epithelial interactions are necessary for proper formation of these organs and tissues. The presence of limb anomalies in approximately one\u2010third of CHARGE syndrome patients fulfills criteria #3 above, in that limb anomalies were not felt to be a part of CHARGE syndrome until relatively recently. It is known that some patients with chromosomal abnormalities have a phenotype that overlaps with CHARGE syndrome. Given that critical developmental pathways must be robust and redundant in order to minimize errors, it may be that disruption of more than one gene is necessary to generate the CHARGE phenotype, as has been proposed for the holoprosencephaly sequence. Mutations and deletions of <jats:italic>CHD7<\/jats:italic> have recently been identified as causing CHARGE syndrome in more than 50% of tested patients. Given this gene classes' putative role as a general controller of developmental gene expression as well as mesodermal patterning, it would fit the hypothesized mechanisms discussed in the study. \u00a9 2005 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.a.30561","type":"journal-article","created":{"date-parts":[[2005,1,6]],"date-time":"2005-01-06T15:48:35Z","timestamp":1105026515000},"page":"318-325","source":"Crossref","is-referenced-by-count":24,"title":["Speculations on the pathogenesis of CHARGE syndrome"],"prefix":"10.1002","volume":"133A","author":[{"given":"Marc 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