Carvalho, C. M. B., Brennand, K., Yuan, B., Sebat, J., Malhotra, D., McCarthy, S., Rudolph, U., Levy, D., Lupski, J. R. (March 2015) Mosaicism May underlie Pleiotropic Psychiatric Phenotypes. Schizophrenia Bulletin, 41. S198-S199. ISSN 0586-76141745-1701
Abstract
Background: Copy number variants (CNVs) involving the 9p region have been observed in patients with SZ, ASD, BPD, and ID. Using a genome-wide copy-number scan (Nimblegen HD2 2.1 M), we identified a ~1.8 Mb duplication-triplication on 9p.24.1 in a proband with a diagnosis of schizo-affective disorder and in his mother, who has a diagnosis of bipolar disorder with psychotic features. Remarkably, the triplicated region includes GLDC and KDM4C; deletions and duplications involving those genes have been observed in ASD cohorts as well as in patients with SZ, BPD or ID. GLDC is the enzyme that catabolizes glycine, a co-agonist of the NMDA receptor (NMDAR). Triplication of GLDC would be expected to accelerate degradation of glycine, resulting in low levels of brain glycine and NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of psychotic disorders. Methods: We designed a custom high density array CGH and further sequenced breakpoint junctions to gain insights into the novel 9p molecular structure. Study of the mRNA from lymphoblastoid cell lines was also performed to check for fusion gene formation. In addition, fibroblasts from proband and mother were obtained and are currently being reprogrammed into human induced pluripotent stem cells (hIPSCs). Results: This rare CNV was confirmed as a de novo event in the mother using a customized high-density Agilent array CGH platform. Sequencing of the CNV breakpoint junctions revealed that this CNV was more complex than originally thought due to the presence of insertions of variable sizes into the junction, including a 65.2 kb segment that was copied from the intron of the nearby gene PTPRD. This rearrangement caused the formation of a fusion gene (UHRF2-KDM4C) as revealed by mRNA expression in the proband. We also found evidence that the mother was mosaic for this de novo rearrangement as the CNV was present in genomic DNA extracted from blood and from her fibroblasts but not in the derived lymphoblastoid cell line or in the derived iPSCs. Conclusion: Breakpoint junction sequencing studies provides valuable information that complements the results of copy-number scans and helps to further characterize structural variants. The mosaicism in the mother may be related to her less severe clinical phenotype. Mosaicism may be a factor in pleiotropic phenotypes as well as variable penetrance.
| Item Type: | Paper |
|---|---|
| Additional Information: | Meeting Abstract |
| Subjects: | diseases & disorders > mental disorders Publication Type > Meeting Abstract |
| CSHL Authors: | |
| Communities: | CSHL labs > McCombie lab |
| Depositing User: | Matt Covey |
| Date: | March 2015 |
| Date Deposited: | 29 May 2015 19:49 |
| Last Modified: | 05 Feb 2018 21:07 |
| URI: | https://repository.cshl.edu/id/eprint/31547 |
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