Whole Exome Sequencing in Early-onset Systemic Lupus Erythematosus

Objective. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder. Early-onset, familial, and/or syndromic SLE may reveal monogenic pathologies. The aim of this study was to examine genetic associations in patients with early-onset or familial SLE. Methods. We enrolled 7 SLE cases (from different families) with disease onset ≤ 5 years of age and family history consistent with an autosomal recessive inheritance. Whole exome sequencing (WES) was performed in 6 index cases. Suspected variants were confirmed by Sanger sequencing. We did not perform WES in 1 patient who had features similar to the first 3 cases; only the exons ofC1QA, C1QB,andC1QCwere screened with Sanger sequencing. Results. We demonstrated 2 novel and 3 previously reported variants in genes associated with SLE: a homozygous non-sense alteration (c.622C>T/p.Gln208Ter) inC1QAin 2 patients; homozygous non-sense alteration (c.79C>T/p.Gln27Ter) inC1QCin 1 (novel variant); homozygous missense alteration (c.100G>A/p.Gly34Arg) inC1QCin 1; homozygous missense alteration (c.1945G>C/p.Ala649Pro) inC1Sin 1 (novel variant); and homozygous frameshift alteration (c.289_290delAC/p.Thr97Ilefs*2) inDNASE1L3in 1 patient. Further, in 1 patient, we determined a strong candidate variant inHDAC7(histone decetylase 7). Conclusion. Five patients had homozygous alterations in genes coding early complement proteins. This may lead to decreased clearance of apoptotic bodies. One patient hadDNASE1L3variant, which functions in the clearance of self-antigens. In 1 patient, we determined a novel gene that may be important in SLE pathogenesis. We suggest that monogenic causes/associations should be sought in early-onset and/or familial SLE.