Molecular mechanisms in 22q11 deletion syndrome

Abstract

It is now well recognized that as well as having a characteristic facial dysmorphology and a range of congenital abnormalities, individuals with chromosome 22q11 deletion syndrome (22q11DS) have a greatly increased risk of developing psychosis, in particular schizophrenia. The majority of deletions span a large 3Mb region at 22q11. However, the presence of affected individuals carrying smaller deletions have not been sufficient to satisfactorily reduce the critical region for the behavioral phenotype beyond a ∼1.5Mb region that contains at least 28 genes. By having a shared genetic variant that greatly increases risk to psychosis, individuals with 22q11DS are a relatively homogeneous population to study psychiatric disease. Despite this, the large volume of research performed over the last 15 years suggest that the mechanism by which haploinsufficiency at 22q11 increases risk to psychiatric illness is likely to be complex and it remains uncertain why individuals carrying identical 22q11 deletions can present with such a wide range of neuropsychiatric phenotypes. This review will therefore consider the ways in which deletions at 22q11 are expected to increase risk to develop psychiatric disease by summarizing the work that has been done to investigate three of the most likely disease causing mechanisms: (a) gene dosage sensitivity; (b) unmasking of recessive alleles or functional polymorphism; and (c) position effect. © 2011 The Author.