Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome. Dev Disabil Res Rev

Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Republic of Ireland.
Developmental Disabilities Research Reviews (Impact Factor: 2.75). 01/2008; 14(1):26-34. DOI: 10.1002/ddrr.5
Source: PubMed


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.

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    • "It is noteworthy that relatively rare subgroups continue to receive study and provide valuable data to schizophrenia research. They include velocardiofacial syndrome (Prasad et al., 2008) and pediatric onset (Clemmensen et al., 2012) patients. "
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    ABSTRACT: The validity and significance of normal range neurocognition in schizophrenia remain unclear and controversial. We assessed whether normal range patients and controls demonstrate evidence of decline relative to premorbid ability and differ in performance profiles across measures, including those external to the normality criterion. In addition, we compared below normal range healthy control participants with patients at the same ability level. Performance normality was defined as a MATRICS Consensus Cognitive Battery (MCCB) composite T score between 40 and 60. Patients (n=17) and controls (n=24) meeting the criterion were compared on MCCB domain scores and on independent measures of reading ability, probabilistic and social reasoning. Patients (n=19) and controls (n=20) scoring below 40 on the MCCB composite were compared on the same set of measures. Cognitively normal range patients and controls did not differ on estimated premorbid ability or decline and differed only on the Processing Speed domain of the MCCB. Performance did not differ across other domains or on social and probabilistic reasoning tasks. Cognitively below normal range patients and controls showed marked discrepancies between premorbid and current ability, but there were no group differences. In addition, below normal range groups did not differ on any MCCB domain score or in terms of external cognitive measures. Cognitively normal range schizophrenia patients may be largely indistinguishable from normal range controls, with the exception of processing speed performance. More typical schizophrenia patients below the normal range may be indistinguishable from low-performing controls even in terms of processing speed.
    Schizophrenia Research: Cognition 11/2015; DOI:10.1016/j.scog.2015.09.001
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    • "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. "
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    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.
    G3-Genes Genomes Genetics 09/2015; 5(11). DOI:10.1534/g3.115.021345 · 3.20 Impact Factor
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    • "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]. "
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    ABSTRACT: Chromosome 22q11.21 contains a cluster of low-copy repeats (LCRs), referred to as LCR22A-H, that mediate meiotic non-allelic homologous recombination, resulting in either deletion or duplication of various intervals in the region. The deletion of the DiGeorge/velocardiofacial syndrome interval LCR22A-D is the most common recurrent microdeletion in humans, with an estimated incidence of ∼1:4,000 births. Deletion of other intervals in 22q11.21 have also been described, but the literature is often confusing, as the terms 'proximal', 'nested', 'distal', and 'atypical' have all been used to describe various of the other intervals. Individuals with deletions tend to have features with widely variable expressivity, even among families. This review concisely delineates each interval and classifies the reported literature accordingly. © 2015 S. Karger AG, Basel.
    Cytogenetic and Genome Research 08/2015; DOI:10.1159/000438708 · 1.56 Impact Factor
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