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Schizophrenia two-hit hypothesis in velo-cardio facial syndrome

Williams, Hywel John, Monks, Stephen, Murphy, Kieran C., Kirov, George, O'Donovan, Michael Conlon and Owen, Michael John 2013. Schizophrenia two-hit hypothesis in velo-cardio facial syndrome. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 162 (2) , pp. 177-182. 10.1002/ajmg.b.32129

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Deletion of chr22q11 gives rise to velo-cardio facial syndrome (VCFS) and increases schizophrenia risk. The source of this elevated risk although unknown could result from stochastic, environmental, or genetic factors, the latter encompassing a range of complexity from polygenic mechanisms to “second-hit” mutations. For this study we tested the two-hit hypothesis where additional risk is conferred through a second CNV. We identified large (>100 kb) CNVs in 48 VCFS cases (23 with psychosis—25 without) and show in the psychotic VCFS group there is a significant (P = 0.02) increase in the average size of CNVs (354–227 kb). To identify second-hit loci we focused on individuals possessing gene-centric CNVs and through literature mining identified 4 (31%) psychotic VCFS individuals (n = 13) that overlapped loci previously implicated in neuropsychiatric disorders compared to 1 (10%) from the non-psychotic VCFS individuals (n = 10). For replication 17 VCFS patients with schizophrenia from the molecular genetics of schizophrenia dataset were used to identify further CNVs. Thirteen individuals possessing gene-centric CNVs were identified including 3 (23%) individuals possessing a potential second-hit, taking the overall total in the psychotic VCFS group (n = 26) to 7 (27%) potential second-hit loci. Notably a deletion in a psychotic VCFS patient at 2q23.1 hit the gene MBD5 which when deleted gives rise to intellectual disability, epilepsy, and autistic features. Through this study we potentially extend this phenotypic spectrum to include schizophrenia. Our results suggest the two-hit hypothesis may be relevant to a proportion of VCFS patients with psychosis but sample sizes are small and further studies warranted.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Schizophrenia; VCFS; CNV; 22qDS.
Publisher: Wiley-Blackwell
ISSN: 1552-4841
Last Modified: 17 Jan 2020 08:57

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