, 2009), where the rare CNV call is assigned a p value based on t

, 2009), where the rare CNV call is assigned a p value based on the distribution of probe ratios across the reference population. Thresholds for CS were then adjusted within each size class of CNV to achieve a 5% rate of mendelian inconsistency across all size classes (Figure S1). Second, we removed rare CNVs which had > 70% overlap with known BKM120 SDs from the UCSC hg18 Human Genome browser annotations. A SD filter is helpful because it eliminates regions where the exact location, boundaries, and patterns of inheritance of the CNV calls are often too difficult to determine from array CGH data due to the complexity of the local genomic architecture. This final rare CNV call sets consisted of 3,856 CNVs in 788 offspring

including BD, SCZ, and controls and in 45 ASD subjects (Table S1). Before examining the parent-child transmission of CNVs in trios, we first confirmed parentage of all trios included in CNV analysis. We used genotypes

from 486 CNPs (see Supplemental Experimental Procedures) to test relatedness. For each pair within a trio (i.e., mother-child, father-child, and mother-father), genetic relatedness was tested by the Glaubitz Relationship Score (GRS) (Glaubitz et al., 2003). Based on this test, first-degree relative pairs (i.e., mother-child and father-child) buy CAL-101 were clearly distinguishable from the distribution of GRS scores for unrelated individuals (i.e., mother-father pairs) as shown in Figure S2. We applied a threshold of > 0.37 to define relatedness. Thirty-two families failed parentage testing, and the remaining 788 trios were included in our analysis. Pairwise relationship of all subjects

in 788 trios was confirmed using a second relatedness testing method, Graphical Resminostat Representation of Relationships (GRR, http://www.sph.umich.edu/csg/abecasis/GRR/). The identification of rare de novo mutations from CNV data on families is nontrivial. While CNV calls that show mendelian patterns of inheritance (which is the overwhelming majority of CNVs in the genome) are quite reliable, the fraction of CNV calls that are present in offspring and not in parents are enriched for technical errors, in particular false-positive calls (in the offspring) and false-negative calls (in parents). In addition, the enrichment of such errors is greater for smaller CNVs. To address these sources of error, we designed a set of algorithms for de novo CNV identification in families. The false-positive CNV call rate was controlled (maintained at 5%) for a wide range of CNV sizes by adaptive filtering of confidence scores (CSs), as described above. In order to minimize the number of false-negative calls in parents, the CNV region was directly genotyped using the MeZOD, and a confidence score was used to assign genotypes to the parents. Rare CNVs in children were called inherited if the CS was ≤ 0.04 in either of the two biological parents and de novo if CS was > 0.04 in both biological parents.

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