opposed to inverted, orientation is a key distinction between active and inactive hotspots (46/54 direct vs. 16/57 inverted; OR = 3.04). We also found that SDs flanking active hotspots are larger and show higher sequence identity compared to inactive hotspots (Kolmogorov-Smirnov test, p = 0.0022) (Supplementary Figure 5). Interestingly, eight regions were identified that showed no evidence of copy number variation in cases or controls despite the presence of large, highly similar, and directly oriented SDs at their flanks (Supplementary Table 10). These may be regions that are mutationally active but in which dosage imbalance is lethal (e.g. 7p14.3 flanked by 19.9 kbp duplications and containing BBS9 and BMPER).
