By performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants.

通过在 71 个亲子三人组的瑞典队列中进行全基因组测序，其中每个家庭的孩子都受到系统性红斑狼疮（SLE，OMIM 152700）的影响，我们调查了 de novo 变异对 SLE 风险的贡献。我们发现，与健康对照相比，SLE 患者的 de novo 单核苷酸变体 (SNV) 的基因启动子显着富集，其水平相当于每个患者中比预期多 26 个 de novo 启动子 SNV。我们在先前与 SLE 相关或具有可能与 SLE 相关的功能的基因的启动子区域中鉴定了 12 个从头 SNV。此外，我们检测到三个错义 de novo SNV、五个 de novo 插入缺失和三个 de novo 结构变异，这些变异可能影响与 SLE 相关的基因的表达。根据富集分析，预计三分之一的 SLE 患者会出现影响疾病的新发 SNV。这项研究表明，启动子中的从头变异通常会导致 SLE 的遗传风险。SLE 中的 de novo SNV 富集到启动子区域这一事实凸显了使用全基因组测序来鉴定 de novo 变异的重要性。