Fig. 4

De novo enrichment and clustering of missense variation analyses of NDD hnRNPs. a De novo variation was assessed for NDD HNRNPs using two statistical models: the CH model and denovolyzeR. Right/above the dotted line indicates the gene achieves exome-wide significance (q < 4.24 × 10^− 7) while right/above the dashed line indicates the gene reaches nominal significance (q < 0.05). HNRNPU reaches exome-wide significance for all protein-impacting variants (Protein) and LGD variants, with severe missense variants reaching significance by only the CH model. SYNCRIP reaches exome-wide significance for LGD variants and all protein-impacting variants by the CH model alone. HNRNPD reaches nominal significance by the CH model. P values are FDR corrected with the number of genes (n = 18,946 for CH model and n = 19,618 for denovolyzeR) with three tests per gene (LGD, missense, and all protein changes) and two tests (CH model and denovolyzeR) per mutation type. Only cohorts with known de novo status were included, as listed in Tables S1 and S7. Statistics can be seen in Table S6. b Analysis of clustered missense variants. Clustering of missense variants was analyzed using CLUMP; scores are shown in Table S6 (paired t-test). Compared to the non-neuropsychiatric subset of gnomAD (n = 114,704, 1958 missense variants), the CLUMP score for NDD hnRNPs (red) among probands is significantly lower than controls in gnomAD (black), indicating more clustering of mutations (shown by arrow). Note that only genes with variants in the current cohort could undergo this analysis. hnRNPH2, hnRNPK, hnRNPR, and hnRNPUL1 each have independent significant clumping compared to gnomAD controls. c CLUMP scores for missense variants in probands with ASD (n = 60). HnRNPH2, hnRNPK, hnRNPR, and hnRNPUL1 reach significance independently. *p < 0.05, **p < 0.01, ***p < 0.001. LGD: likely gene disrupting; Missense: severe missense (CADD ≥ 20); Protein: all protein-affecting variants