Fig. 4

Enrichment of “second-hit” variants near genes with outlier expression. A Forest plot shows enrichment (Fisher’s exact test, ** = FDR < 0.05, * = uncorrected p < 0.05) of genes with outlier expression in all individuals in the cohort (n = 32) for rare proximal coding and non-coding variants, including single-nucleotide variants (SNVs) and insertions/deletions (indels) with CADD scores > 10 [37], structural variants (SVs), and short tandem repeats (STRs). B Forest plot shows classes of “second-hit” variants with significant enrichment (Fisher’s exact test, ** = FDR < 0.05, * = uncorrected p < 0.05) towards genes with outlier expression in carrier children (n = 10), carrier parents (n = 6), or noncarrier parents (n = 6). C Forest plot shows classes of “second-hit” variants with significant enrichment (Fisher’s exact test, ** = FDR < 0.05, * = uncorrected p < 0.05) towards genes with outlier expression in carrier children (n = 9) that are shared with either carrier or noncarrier parents. All forest plots show log-odds ratios (dots) and 95% confidence intervals (whiskers). Odds ratios, confidence intervals, p values, and Benjamini-Hochberg corrected FDR values for comparisons with all classes of “second-hit” variants are listed in Additional file 4: Data S2. D Scatter plot shows expression values (transcripts per million, or TPM) for EIF2AK1 in LCL replicates for all individuals (n = 32). Samples in blue have outlier expression of EIF2AK1 (z-score < − 2) and carry a deleterious “second-hit” variant in the 5′ UTR of the gene. E Scatter plots show expression values (TPM) of genes with synergistic effects due to the 16p12.1 deletion and inherited “second-hit” variants. Blue circles indicate expression values for samples from carrier children and family members with rare “second-hit” variants, orange circles indicate expression values for samples from family members without the “second-hit” variant, and green circles indicate expression values of samples from other deletion carriers and noncarriers in the cohort. Black lines denote median gene expression for LCL replicates of each individual used to identify genes with outlier expression in individual deletion carriers