One of the most common genomic hotspots in this study is 15q11.2 (NIPA1), a 292 kbp deletion whose pathogenicity has been considered uncertain4,20. In terms of frequency, the 15q11.2 deletion is second only to VCF/DGS deletion, and our data indicate it is significantly enriched (OR = 2.36, p = 2.5×10−5) albeit at lower penetrance (0.83) than most other genomic disorders. In addition, we find support for the pathogenicity of duplications of obesity-associated 16p11.2 (SH2B1)21,22 and epilepsy-associated 15q13.3 (CHRNA7)23. We also analyzed 111 regions of the human genome predicted to be prone to recurrent microdeletions and microduplications based on the presence of homologous SDs at their flanks in the reference assembly6. Of these potential hotspots, 62 harbored CNVs likely mediated by NAHR between the flanking SDs (“active hotspots”), while the remaining 49 did not. The presence of SDs in direct, as 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
