Abstract The omnigenic model of complex diseases 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 (WES), high-density imputation, and in vitro cellular assays, we identify three 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 &gt;80 SLE susceptibility loci implicated through genome-wide association studies (GWAS). 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. 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). Both genes are functional candidates and significantly constrained against missense mutations in gene-level analyses, along with C1QTNF4 . We further characterise the TNF-dependent functions of candidate gene C1QTNF4 on NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation. Significance Statement Rare variants, present in &lt;1% in population, are expected to explain little of the heritability of complex diseases, such as Systemic Lupus Erythematosus (SLE), yet are likely to identify core genes crucial to disease mechanisms. Their rarity, however, limits the power to show their statistical association with disease. Through sequencing the exomes of SLE patients and their parents, we identified non-inherited de novo mutations in 14 genes and hypothesised that these are prime candidates for harbouring additional disease-associated rare variants. We demonstrate that two of these genes also carry a significant excess of rare variants in an independent, large cohort of SLE patients. Our findings will influence future study designs in the search for the ‘missing heritability’ of complex diseases.

De novomutations implicate novel genes with burden of rare variants in Systemic Lupus Erythematosus