Randall, V.A.; (2009) Investigation into the phenotypic and genetic overlap between CHARGE and DiGeorge syndromes during development of the pharyngeal apparatus. Doctoral thesis , UCL (University College London).

Abstract

CHARGE and DiGeorge (DGS) are multiple malformation haploinsufficiency syndromes that show significant phenotypic overlap, especially when considering derivatives of the pharyngeal apparatus. Patients exhibit characteristic cardiovascular malformations including anomalies associated with defective patterning of the pharyngeal arch arteries (paa). CHD7, on chromosome 8q12.1, was recently identified as a candidate gene for CHANGE and is mutated in ~60% of patients. Most DGS patients carry a 3Mb heterozygous deletion of chromosome 22q11, encompassing ~30 genes including TBX1. Animal models of DGS have demonstrated the importance of Tbx1 during pharyngeal and heart development. The critical role of TBX1 in DGS is supported by the identification of TBX1 mutations in DGS patients without 22q11 deletions. CHARGE and DGS exhibit overlapping genetic etiologies. Patients diagnosed with CHARGE can have 22q11 deletions, while complete DGS can be found in patients with CHD7 mutations. However, despite the genetic overlap between the two human conditions, work presented here failed to identify CHD7 mutations in a cohort of non-deleted patients. Results presented in this thesis show that insertion of a gene trap cassette, disrupting CHD7, produced a mouse model of CHARGE consistent with the human condition. Chd7^{+/-} embryos exhibited heart defects resulting from aberration of the paa, including interrupted aortic arch type-B. Chd7 is only the second gene reported, after TBx1, heterozygous mutations of which cause fourth paa defects. Furthermore, the phenotype of Chd7^{+/-} animals demonstrated epistasis between the two genes during formation of the fourth paa and thymus. Contrary to hypotheses suggesting CHARGE is the result of genetic deficiencies in neural crest cells (NCC), conditional Wnt1-Cre driven restoration of Chd7 expression in NCC, did not prevent paa defects. AP2 \propto –Cre driven restoration of Chd7 expression in the ectoderm and NCC simultaneously, rescued the paa defects, identifying a requirements for Chd7 expression in the ectoderm during development of these vessels.

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