Here, we show that rare de novo copy-number mutations are significantly enriched in bipolar disorder and in schizophrenia. Our study sample included 788 subject-mother-father trios with confirmed parentage. DNA from all subjects was derived from whole blood. Details of the subjects are described

in the Supplemental Experimental Procedures (available online). Diagnoses of subjects included bipolar disorder (n = 185, including 107 with an age at onset ≤ 18), schizophrenia (n = 177), and healthy controls (n = Selleckchem MLN0128 426). While the primary disease focus of this study was BD, the inclusion of an additional schizophrenia cohort served first to replicate the one previous study of de novo CNVs in SCZ (Xu et al., 2008) and second to enable a valid comparison of patterns of de novo CNVs in BD with another disorder. In addition, a small set of autism spectrum disorder (ASD) trios (n = 45), all of which had been included in a previous study (Sebat et al.,

2007) and three of which carried known de novo CNVs, were included as a “positive control” to confirm the sensitivity of our methods for detecting de novo events. We performed high-resolution genome-wide copy-number scans, using the NimbleGen HD2 array comparative genomic hybridization (CGH) platform, on all subjects and their biological parents. Data processing and CNV detection were performed buy Dabrafenib as described in Experimental Procedures. CNV call sets were filtered based on probe ratio (≤0.8 and ≥ 1.2), number of probes (≥10), frequency (<1%), and confidence score (Supplemental Experimental Procedures, Tables S1 and S2, and Figures S1 and S2). Rare CNVs that were present in subjects and not in their parents were subsequently validated and fine mapped using a custom tiling-resolution CGH array (Oxford Gene Technology) (Table S3. Custom Tiling arrayCGH Validation of Putative De Novo CNVs and Document

S1. Figures S1–S3; Tables S1, S2, S4–S8, and S10; and Supplemental Experimental Procedures). Results for the genome-wide scans, tiling array validations, and breakpoint sequencing are illustrated by four examples: a deletion involving much CMIP and PLCG2 genes ( Figure 1I) and an exonic deletion of LINGO2 gene ( Figure 1II) detected in subjects with a diagnosis of BD, and an intronic deletion of CSMD3 gene ( Figure 2I) and a deletion adjacent to UGT8 gene ( Figure 2II) detected in subjects with a diagnosis of SCZ. A total of 23 de novo CNVs were detected and validated in our study sample, including fourteen deletions and nine duplications (Table 1). De novo CNVs ranged in size from 15.1 to 7,178 kb, with a median size of 112 kb, and contained a median of two genes. About one-third (8/23) of de novo CNVs in our study were flanked by segmental duplications (SDs) at one (6/23) or at both boundaries (2/23).