Fig. 1: Overview of study design.
From: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Targeted sequencing was performed in probands for two gene panels: NDD1 (63 genes) and hcNDD (62 genes). Gene and variant counts are after QC. The same categories of variants were retrieved from three previously published smMIP studies for 62 hcNDD genes. All smMIP variants were combined; redundant samples were eliminated and compared to the same category of variants from ExAC non-psych controls. The number of variants is after the exclusion of false positive variants and variants with insufficient coverage in ExAC. Mutation burden analysis identified 48 FDR significant genes (qmutBurden < 0.05, Benjamini–Hochberg correction for 125 genes), of which six reached FWER significance (pmutBurden < 1.25E−06, Bonferroni correction for 20,000 genes and two tests); DNMs of the 125 genes used in this study were identified from exome sequencing in 10,927 published NDD trios and 6,499 new ASD trios that combined as 17,426 NDD parent–child trios. A separate de novo enrichment analysis, using two statistical methods (CH model and denovolyzeR), identified 90 FDR significant genes (qdnEnrich < 0.05, Benjamini–Hochberg correction for 18,946 genes in CH model and 19,618 genes in denovolyzeR), of which, 61 genes reach FWER significance (pdnEnrich < 3.64E−07, Bonferroni correction for 19,618 genes and seven tests) for excess DNM. There is a significant overlap (40 genes) of the significant genes suggested by the two approaches. Then we performed genotype–phenotype correlation analysis for seven NDD risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) and present a clearer clinical picture of each gene.
