Background/Purpose:

Next generation sequencing (NGS) represents a revolution in the field of molecular medicine, and offers a new approach to deciphering the pathogenesis of complex diseases. Paediatric-onset SLE (pSLE) is a very rare and more severe phenotype than its adult-onset counterpart, and is possibly associated with a greater contribution of genetic aetiological factors. A few monogenic causes of SLE have been described, including: complement deficiencies, defects of apoptosis and the so-called interferonopathies. The frequency of these Mendelian subtypes in a large cohort of pSLE has not been assessed previously.

Methods:

We designed an NGS panel comprising 200 genes including proven disease-associated as well as prospective candidate genes, and analysed 85 children under 11 years of age who fulfilled ACR criteria for SLE. As a first step, we focussed on rare (ExAC database frequency of < 1% for homozygous variants and < 0.01% for heterozygous variants) null / frameshift variants, and missense substitutions predicted in silico as damaging by both SIFT and POLYPHEN.

Results:

We identified three patients with biallelic mutations in genes of the complement pathway – one with a homozygous missense variant (p.Gly164Ser) and one with compound heterozygous variants (p.Gly164Ser/p.Leu41CysfsTer97) in C1QC, and one with a homozygous frameshift variant (p.Ile15AsnfsTer7) in C1QA. Four further patients harboured heterozygous variants (in C1QC, C2, C5 and C9) which were predicted as pathogenic. Copy number variant analysis in these genes has not yet been undertaken. A TREX1 p.Ser82LeufsTer9 variant, previously observed in a patient with Aicardi-Goutières syndrome, was identified in one patient in combination with a missense variant of unknown significance. One patient carried a heterozygous variant in ACP5 – predicted as pathogenic by in silico analysis but not seen previously in SPENCD. In total, 11 patients harboured heterozygous rare variants in 2 or 3 panel genes (8 and 3 patients respectively). No likely pathogenic variants were identified in DNASE1, DNASE1L3 or PRKCD.

Conclusion:

This first-step analysis of candidate gene variants in a population of 85 pSLE patients revealed three cases of C1Q deficiency – associated with a 1 in 4 risk of recurrence, and which had not been diagnosed previously. The significance of heterozygous variants in other genes is difficult to determine at this stage. The association of 2 / 3 very rare heterozygous variants in a single patient raises the possibility of an oligogenic burden in the pathogenesis of pSLE. Functional experiments are mandatory to understand the impact of these rare variants. Future work will also involve increasing the number of patients analysed, and consideration of intronic and splicing variants. However, we already conclude that an NGS panel approach can diagnose unappreciated monogenic forms of pSLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ngs-panel-for-the-detection-of-monogenic-sle-in-children-initial-results/