While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten pathogenic CNVs and 20 neurodevelopmental genes in Drosophila melanogaster. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including 21 lines with severe wing defects and six lines with lethality. In fact, we found that 10/31 homologs of CNV genes also showed complete or partial lethality at larval or pupal stages with ubiquitous knockdown. Comparisons between eye and wing-specific knockdown of 37/45 homologs showed both neuronal and non-neuronal defects, but with no correlation in the severity of defects. We further observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further supported by tissue-specific differences in expression patterns of human CNV genes, as well as connectivity of CNV genes to signaling pathway genes in brain, heart and kidney-specific networks. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.

虽然罕见的致病性拷贝数变异（CNV）与神经元和非神经元表型都相关，但评估这些区域的功能研究却集中在神经元缺陷的分子基础上。我们报告了十个致病性CNVs中的59个基因的同源物和果蝇的20个神经发育基因的非神经元缺陷的系统功能分析。。使用特定于机翼的136个RNA干扰系的敲低，我们在72/79个同系物中鉴定了定性和定量表型，包括21个具有严重机翼缺陷的系和6个具有致死性的系。实际上，我们发现CNV基因的10/31同源物在幼虫或p期普遍杀灭也显示出完全或部分杀伤力。眼和机翼特异性击倒37/45同源物之间的比较显示神经元和非神经元缺损，但缺损的严重程度没有相关性。我们进一步观察到23/27个同源物的幼虫翼盘细胞增殖和凋亡受到破坏，而9/14个同源物（包括AATF / Aatf，PPP4C / Pp4-19C和KIF11 / Klp61F）的Wnt，Hedgehog和Notch信号改变。这些发现还得到了人类CNV基因表达模式的组织特异性差异以及脑，心脏和肾脏特异性网络中CNV基因与信号通路基因的连通性的进一步支持。我们的发现表明，每个CNV中的多个基因差异地影响了保守途径中的全局和组织特异性发育过程，并且它们的作用并不局限于神经元功能。