There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk for the development of schizophrenia, with only a greater risk conferred by being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual. Both linkage and association studies of people with schizophrenia have implicated several susceptibility genes, of which three are in the 22q11.2 region; catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH), and Gnb1L. In addition, variation in Gnb1L is associated with the presence of psychosis in males with 22q11.2DS. In mouse models of 22q11.2DS, haploinsufficiency of Tbx1 and Gnb1L is associated with reduced prepulse inhibition, a schizophrenia endophenotype. The study of 22q11.2DS provides an attractive model to increase our understanding of the development and pathogenesis of schizophrenia and other psychiatric disorders in 22q11.2DS and in wider population.
"have shown conflicting or negative results, however reduced gene dosage of neurofunctional genes within the 22q11.2 region may contribute to schizophrenia risk (Philip and Bassett 2011; Arinami 2006; Prasad et al. 2008; Karayiorgou et al. 2010). Although we did not identify rare variants disrupting candidate genes Merico et al. "
[Show abstract][Hide abstract] ABSTRACT: Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of DGCR8 haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high quality whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal p=0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a DGCR8 mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic non-coding RNA genes were also enriched in the schizophrenia group (nominal p=0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and non-coding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes.
"Candidate critical genes for major features of DGS are thought to include HIRA , TBX1 and COMT [McDonald- McGinn et al., 1999; Lindsay et al., 2001; Kessler-Icekson et al., 2002; Bearden et al., 2004; Prasad et al., 2008; Chen et al., 2014; Ogata et al., 2014]. CRKL is considered a candidate critical gene for the central deletions [Racedo et al., 2015], and MAPK1/ERK2 for the distal type I deletions [Saba-El-Leil et al., 2003; Binétruy et al., 2007; Newbern et al., 2008; Samuels et al., 2008]. "
"Most recombination events occur between LCRs A and D, giving rise to the common 3 Mb deletion. Approximately 8% of patients have a 1.5 Mb deletion, nested within the 3 Mb deletion.20,54,56 It has been argued that the 1.5 Mb deletions contain all key genes responsible for the syndrome and, in particular, for the increased risk of psychiatric illness.5,57 "
[Show abstract][Hide abstract] ABSTRACT: The 22q11.2 deletion syndrome (22q11DS) is caused by an autosomal dominant microdeletion of chromosome 22 at the long arm (q) 11.2 band. The 22q11DS is among the most clinically variable syndromes, with more than 180 features related with the deletion, and is associated with an increased risk of psychiatric disorders, accounting for up to 1%-2% of schizophrenia cases. In recent years, several genes located on chromosome 22q11 have been linked to schizophrenia, including those encoding catechol-O-methyltransferase and proline dehydrogenase, and the interaction between these and other candidate genes in the deleted region is an important area of research. It has been suggested that haploinsufficiency of some genes within the 22q11.2 region may contribute to the characteristic psychiatric phenotype and cognitive functioning of schizophrenia. Moreover, an extensive literature on neuroimaging shows reductions of the volumes of both gray and white matter, and these findings suggest that this reduction may be predictive of increased risk of prodromal psychotic symptoms in 22q11DS patients. Experimental and standardized cognitive assessments alongside neuroimaging may be important to identify one or more endophenotypes of schizophrenia, as well as a predictive prodrome that can be preventively treated during childhood and adolescence. In this review, we summarize recent data about the 22q11DS, in particular those addressing the neuropsychiatric and cognitive phenotypes associated with the deletion, underlining the recent advances in the studies about the genetic architecture of the syndrome.
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