Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder with different genetic and environmental factors playing role in its pathogenesis. Early onset SLE, familial SLE, and syndromic SLE are rare situations which may lead to identification of monogenic defects responsible for the disease. Identification of monogenic causes through these cases can help us to understand the pathogenic mechanisms in SLE. We aimed to discover monogenic defects causing SLE by performing whole exome sequencing (WES) in familial or early-onset SLE cases.
Methods: We enrolled 12 pediatric SLE cases (from 7 different families) who had disease onset before 5 years of age and a family history consistent with an autosomal recessive inheritance (affected siblings or parenteral consanguinity). Whole exome sequencing and bioinformatic analyses were performed in six index cases and the suspected mutations were confirmed by Sanger sequencing. Only C1Q gene was analyzed by Sanger sequencing in patient 4 since he had similar features with the first three cases.
Results: There was consanguinity in all families. The characteristics of index SLE cases are presented in Table 1. We have demonstrated a homozygous nonsense mutation (c.622C>T/p.Gln208Ter) in C1QA gene in 2 patients; homozygous nonsense mutation (c.79C>T/p.Gln27Ter) in C1QC gene in 1; homozygous missense mutation (c.100G>A/p.Gly34Arg) in C1QC gene in 1; homozygous stop codon mutation (c.1945G>C/p.Ala649Pro) in C1S gene in 1; homozygous frameshift mutation (c.290_291delCA/p.Thr97Ilefs*2) in DNASE1L3 gene in 1 patient. There was a candidate novel gene in 1 patient and functional studies on this gene are ongoing.
Conclusion: Five of our patients had homozygous mutations in the genes coding for early complement proteins. The risk to develop pediatric SLE is estimated to be 93% for C1q and 66% for C1s/r defects. There are around 100 published cases with homozygous C1q deficiency. The clinical presentations are variable; however, they usually had cutaneous involvement, normal C3, C4 levels and negative anti-dsDNA which was the case in our patients. C1s deficiency is much rarer. The nonsense mutation in C1S gene of our patients was novel. DNASE1L3 gene encodes for DNase1 enzyme which functions as an endonuclease cleaving DNA. Deletion in DNASE1L3 gene has been previously reported to be associated with SLE in the study on 7 SLE families where it was shown that protein encoded by the mutant DNASE1L3 completely lacked DNase activity. We suggest that monogenic causes/associations should be sought for an early-onset SLE.
|Characteristics||Patient 1||Patient 2||Patient 3||Patient 4||Patient 5||Patient 6||Patient 7|
|Lupus in sibling||+||+||–||–||+||–||+|
|Mutant genes||C1QA||C1QC||C1QC||C1QA||C1S||DNASE1L3||Candidate novel gene|
|Decrease in C3, C4||–||–||–||–||+||+||+|
|Other positive utoantibodies (all patients were positive for ANA)||Anti-SM||Rheumatoid factor||Anti-SM, SSA, lupus antivoagulant||Anti-SM, U1 RNP||AntidsDNA, SSA, U1 RNP, anti-histon||Anti-dsDNA, Anti-cardiolipin||Anti-dsDNA, direct Coombs|
To cite this abstract in AMA style:Batu ED, Kosukcu C, Taskiran EZ, Akman S, Ozturk K, Sozeri B, Unsal E, Ekinci Z, Bilginer Y, Alikasifoglu M, Ozen S. Whole Exome Sequencing in Early Onset Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/whole-exome-sequencing-in-early-onset-systemic-lupus-erythematosus/. Accessed January 28, 2022.
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