Trio whole exome sequencing in Chinese childhood-onset lupus reveals novel candidate genes.

OBJECTIVES Systemic lupus erythematosus (SLE) is an autoimmune disease in which rare and common gene variants contribute to pathogenesis. Severe sporadic disease in children is often explained by 'de novo' variants that can be uncovered by trio sequencing. METHODS Whole exome sequencing was performed in 50 Chinese trios with childhood-onset SLE (cSLE). Rare coding variants in SLE-associated genes and all de novo variants were investigated. Gene pathway and expression analysis, and interferon-β luciferase assays were used to predict contribution to disease. RESULTS Each proband carried at least one rare variant in an SLE-associated gene with a median of six per child. At least two probands had monogenic disease and one third carried novel or rare variants in genes well accepted to cause monogenic SLE: ACP5, C3, C4A, C4B, DNASE1, IFIH1, NRAS, RNASEH2B, RNASEH2C and SAMHD1. Probands carried a median of one de novo, rare, coding variant. Intriguingly, although only 2 de novo variants occurred in genes previously associated with SLE, 12 of the 50 genes were enriched in the top 20 SLE-related pathways and were highly expressed in ABC/plasma B cells. These genes represent promising candidate lupus genes. Two de novo variants occurring in genes not previously linked to SLE or autoimmunity, DHX8 and ACTR5, enhanced type I IFN signaling. CONCLUSIONS This study highlights the abundance of lupus-relevant rare gene variants in cSLE, supports frequent contribution of de novo variants to disease, and identifies genes that may constitute novel therapeutic targets of relevance to Chinese patients.