Genome-wide copy number variation
Table summarizes the 22q11.2DS-related deletions observed in this study. Table summarizes CNVs detected elsewhere in the genome. We found no evidence for an excess of CNVs or any specific targeted CNV regions in subjects with 22q11.2DS and schizophrenia, or in 22q11.2DS overall compared with controls. We were also able to compare the CNV content between 65 unaffected parents in whom de novo
22q11.2 deletions were confirmed not to have arisen and 53 unaffected parents on whose chromosome 22 the 22q11.2 deletions were confirmed to have arisen as de novo
events. These analyses showed no significant differences between these two groups of parents in number, size and proportion of losses of genome-wide CNVs (Supplementary Material, Table S1
22q11.2 deletions in 94 adult probands with 22q11.2 deletion syndrome (22q11.2 DS)
Genome-wide copy number variants (CNV) in 22q11.2 deletion syndrome (22q11.2 DS) with and without schizophrenia and in unaffected parents
There was only one confirmed de novo
CNV outside the 22q11.2 region (a 636 kb gain at 4q35.1) that occurred in a non-psychotic 22q11.2DS proband. This is within the expected rates, given a de novo
mutation rate of approximately 1% at this resolution of analysis in control populations (15
). Inspection of approximately 100 inherited CNVs in subjects with 22q11.2DS revealed on average fewer regions of interest in this study than in our recent study of autism spectrum disorders (16
). There was a novel recurrent/overlapping CNV at 18p11.31 in four subjects with 22q11.2DS and schizophrenia, three with 8.5–10 kb losses that were not validated with quantitative polymerase chain reaction (qPCR) and one with a confirmed 338 kb gain inherited from an unaffected parent. Although a possible region of interest for psychotic disorders (17
), the CNV region contained no genes. Supplementary Material, Tables S2 and S3
show all CNVs, besides the major 22q11.2 deletion, in subjects with 22q11.2DS and their unaffected parents, respectively.
22q11.2 deletions and related copy number variations
The majority (83/94; 88.3%) of probands with 22q11.2DS had the common 3 Mb 22q11.2 deletion. The other 11 probands carried one of eight variants of the 22q11.2 deletion (Table ). Single nucleotide polymorphism (SNP) array results broadly agreed with qPCR results previously published for 44 of the subjects (7
) (Table ). Subjects with schizophrenia carried the typical (39/44; 88.6%) or one of the three variant 22q11.2 deletion breakpoints.
We also examined the 22q11.2 deletion region for CNVs that could predispose to deletion formation. As expected in this region, there were polymorphic CNVs in some parents, including two on whose chromosome the deletion had arisen. A rare 142 508 bp loss (17 269 780–17 412 288), involving the typical 22q11.2 deletion's proximal breakpoint, was found with one algorithm in a proband and unaffected father on whose chromosome arose the 22q11.2 deletion with an atypical proximal breakpoint about 360 kb distal at 17 774 335 (Atypical 1, Table ). The rarity of this CNV in control populations (0.2–0.8%) (16
) makes it possible that it was a factor in the origin of this atypical deletion which is estimated to comprise <1% of all 22q11.2 deletions identified (6
). However, there was no evidence that this or any other CNV in the 22q11.2 region predisposed to other 22q11.2 deletion events.
Parental origin of 22q11.2 deletions and expression of schizophrenia
Expression of schizophrenia was not related to inherited or de novo status of 22q11.2 deletions. Of the probands with inherited 22q11.2 deletions (Fig. ), three of seven (42.9%; one confirmed, two probable) had schizophrenia. Of the 65 probands with confirmed de novo deletions (Table ), in whom parental origin of deletion could be resolved for 60 (Fig. ), there were no significant differences in parental origin of de novo 22q11.2 deletion between the schizophrenia (14/26, 53.9% maternal) and non-psychotic groups (22/34, 64.7% maternal; χ2 = 0.72, df = 1, P = 0.39), or in mean intellectual level (IQ) between probands with maternal or paternal origin of de novo 22q11.2 deletion (70.8, SD 7.9 versus 71.9, SD 9.5, respectively; t = −0.48, df = 22, P = 0.63). IQ results were similarly non-significant within the schizophrenia sub-group (data not shown).
Figure 1. 22q11.2DS, copy number variants (CNVs) and parental origin of deletion. Summary of samples used for genome-wide CNV analyses and of results for analyses of parental origin of 22q11.2 deletions. Confirmed results for parental origin of deletion are based (more ...)
Other factors examined also showed no evidence that they significantly affected risk for schizophrenia in 22q11.2DS. In first-degree relatives, with fluorescence in situ hybridization (FISH) data confirming no 22q11.2 deletion, there was a family history of psychotic illness in two of 44 (4.5%) subjects with schizophrenia and one of 56 (1.8%) in the non-psychotic group. There were no significant differences between these groups in maternal or paternal age (data not shown).
Sex distribution and parental origin of 22q11.2 deletions
Table shows the sex distribution of probands with confirmed de novo 22q11.2 deletions and known parental origin. As previously observed in 22q11.2DS, we found a non-significant excess of de novo maternal deletions (60%; P = 0.12). Further analyses showed that this was associated with sex of the offspring, with males significantly less likely than females to have a de novo 22q11.2 deletion of paternal origin [relative risk (RR) = 0.44, 95% CI = 0.20–0.94; P = 0.019]. This appeared to be due to an unexpected paucity of males with deletions arising on paternally inherited chromosomes (Table ). Results were similar for an expanded sample (Fig. ) including nine subjects with ‘probable’ de novo origin of 22q11.2 deletion (RR = 0.47, 95% CI = 0.25–0.91; P = 0.014). Similar rates of subjects with schizophrenia were present in all four of the possible groups (data not shown) and there was no significant difference in sex distribution between the schizophrenia (20 male, 24 female) and non-psychotic (24 male, 32 female) 22q11.2DS groups (χ2 = 0.07, df = 1, P = 0.80).
Confirmed parental origin of de novo 22q11.2 deletions and sex distribution in 22q11.2 deletion syndrome (22q11.2 DS)
We expanded our examination of skewed sex distribution to include unaffected full sibling live births. Tests of equal proportions showed no significant differences in the six families with male probands of paternal de novo origin 22q11.2 deletions (three brothers, five sisters), 18 families with female probands of paternal origin (18 brothers, 21 sisters), 16 with female probands of maternal origin (14 brothers, 16 sisters) and 20 families of male probands of maternal origin (18 brothers, 14 sisters). There were also no significant differences in maternal or paternal age between subjects with maternal or paternal de novo origin of deletion overall or when male and female probands were examined separately (data not shown).