Chromosomal microdeletions: dissecting del22q11 syndrome

Key Points The most common chromosomal microdeletion syndrome in humans is the chromosome 22 deletion ( del22q11 ). It comprises DiGeorge syndrome, velocardiofacial syndrome and conotruncal anomaly face syndrome, which share a common microdeletion ( del22q11 ) in the proximal long arm of chromosome 22. Approximately 90% of patients have a typically deleted region (TDR) of ∼3Mb, which encompasses ∼30 genes. The lack of variety in deletion size is probably due to the presence of intrachromosomal low-copy repeats (LCRs) flanking the deleted region, which mediate aberrant homologous recombination and unequal crossing-over events between LCR sequences. Despite the genetic homogeneity of the syndrome, the distinct clinical features of the disorder are incompletely penetrant and show variable expressivity. The rare patients who have different deletions or rearrangements in the 22q11 region have not aided the localization of disease genes because some of their rearrangements are non-overlapping. To overcome this paucity of informative human material, mouse models of del22q11 syndrome have been generated using chromosome-engineering techniques to generate deletions in the mouse genome that encompass subsets of the genes deleted in patients. These studies have pointed to genes that might be involved in the del22q11 -like cardiovascular defects seen in mice that harbour some of these. Cardiovascular defects in mice carrying del22q11 -like deletions were rescued by a transgene that contains Tbx1 . Targeted inactivation of Tbx1 showed that its loss produces a phenotype that is similar to a severe del22q11 syndrome phenotype. These chromosome-engineering and gene-knockout studies have identified Tbx1 as a gene that is vital for cardiovascular and pharyngeal development in the mouse. Mutations in the human TBX1 gene have not yet been found in patients that have the clinical features of del22q11 syndrome but not the characteristic deletion, so TBX1 remains a candidate disease gene for the disorder, albeit a tantalizing one. Together these studies have shed light on how disturbed pharyngeal tissue development might underlie many of the clinical features of the del22q11 syndrome, and of the role of Tbx1 in pharyngeal tissue growth and patterning. They indicate that neural crest cells do not have a principal role in the Tbx1 mutant phenotype in the mouse, and are therefore possibly not involved in the pathogenesis of del22q11 , although they might be targets of Tbx1 signalli