| 研究実績の概要 |
Among structural variants, 22q11.2 deletion is one of the highest risk factors for developing schizophrenia. Caused by hemizygous microdeletions at chromosome 22q11.21, about a fourth of the carriers develop schizophrenia. This chromosomal region is considered to be one of the main schizophrenia susceptibility loci, harbouring several candidate genes for disease pathogenesis. The incomplete penetrance of schizophrenia in 22q11.2 deletion suggests polygenic mechanisms that require additional genomic variants outside of the deleted region. This study aimed to decipher the role of genetic defects outside of the 22q11.2 region in increasing the risk for schizophrenia. We performed whole exome sequencing on two individuals with 22q11.2 deletion; one carrier (Person A) with schizophrenia and the other (Person B) who was psychosis-free.
The FISH analysis and aCGH confirmed the 22q11.2 microdeletions, showing a 2.6Mb hemizygous genomic deletion in both participants. The exome sequencing yielded a large number of variants in both participants including the previously reported frameshift mutation in GLO1 in Person A. Based on the specified criteria for variant prioritisation, we identified five heterozygous variants (three frameshift and two nonsense variants) in Person A, which were validated by Sanger sequencing. Interestingly, none of the genes harboring these variants was previously reported to be associated with any neurological or psychiatric phenotypes, and therefore the roles of these genes in manifesting or modulating psychiatric phenotypes warrant future examination.
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