The omnigenic model of complex disease stipulates that the majority of the 
heritability will be explained by the effects of common variation on genes in 
the periphery of core disease pathways. Rare variant associations, expected to 
explain far less of the heritability, may be enriched in core disease genes and 
thus will be instrumental in the understanding of complex disease pathogenesis 
and their potential therapeutic targets. Here, using complementary whole-exome 
sequencing, high-density imputation, and in vitro cellular assays, we identify 
candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). 
Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE 
parent-affected-offspring trios and identified 14 genes with missense de novo 
mutations (DNM), none of which are within the >80 SLE susceptibility loci 
implicated through genome-wide association studies. In a follow-up cohort of 10, 
995 individuals of matched European ancestry, we imputed genotype data to the 
density of the combined UK10K-1000 genomes Phase III reference panel across the 
14 candidate genes. Gene-level analyses indicate three functional candidates: 
DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD 
associated with SLE risk (P = 0.0028), and across DNMT3A associated with two 
severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further 
characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on 
NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our 
results identify three novel genes in SLE susceptibility and support 
extreme-phenotype sampling and DNM gene discovery to aid the search for core 
disease genes implicated through rare variation.