Figure 2

Comparison of predicted gene expression between unaffected variant-transmitting parents and their undiagnosed children with an NDD. (A) Schematic figure depicting how cis-eQTLs may modify the penetrance of a putatively damaging variant transmitted from an unaffected parent to their undiagnosed child in a gene with a LoF mechanism. The haplotype with the ‘+’ symbol has higher predicted expression based on its cis-eQTLs, whereas the one with the ‘−’ symbol has lower predicted expression. (B) Mean difference (parent–child) in predicted gene expression between parents transmitting putatively damaging variants and their children with an undiagnosed NDD, with lines indicating 95% confidence intervals. N denotes the number of unique child-parent pairs. Predicted gene expression can be interpreted as the inverse quantile-normalised number of reads per kilobase of transcript per million mapped reads (RPKM). The three panels show results for putatively damaging variants in three different sets of genes: dominant DD-associated genes with a LoF mechanism (left), recessive DD-associated genes with a LoF mechanism (middle) or constrained genes (pLI > 0.9) (right). Red and blue dots represent results from genetically-predicted gene expression imputed from whole blood and cortex, respectively. We show estimates considering only PTVs, as well as PTVs and missense variants (with MPC ≥ 2) together.