Whole Exome Sequencing in Early-onset Systemic Lupus Erythematosus.

Abstract

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. 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 of <i>C1QA, C1QB,</i> and <i>C1QC</i> were screened with Sanger sequencing. We demonstrated 2 novel and 3 previously reported variants in genes associated with SLE: a homozygous non-sense alteration (c.622C>T/p.Gln208Ter) in <i>C1QA</i> in 2 patients; homozygous non-sense alteration (c.79C>T/p.Gln27Ter) in <i>C1QC</i> in 1 (novel variant); homozygous missense alteration (c.100G>A/p.Gly34Arg) in <i>C1QC</i> in 1; homozygous missense alteration (c.1945G>C/p.Ala649Pro) in <i>C1S</i> in 1 (novel variant); and homozygous frameshift alteration (c.289_290delAC/p.Thr97Ilefs*2) in <i>DNASE1L3</i> in 1 patient. Further, in 1 patient, we determined a strong candidate variant in <i>HDAC7</i> (histone decetylase 7). Five patients had homozygous alterations in genes coding early complement proteins. This may lead to decreased clearance of apoptotic bodies. One patient had <i>DNASE1L3</i> variant, 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.