Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts

Alexandre Belot, Gillian Rice, Omarjee Sulliman Ommar, Quentin Rouchon, Eve M D Smith, Marion Moreews, Maud Tusseau, Cecile Frachette, Raphael Bournhonesque, Nicole Thielens, Christine Gaboriaud, Isabelle Rouvet, Emilie Chopin, Akihiro Hoshino, Sylvain Latour, Bruno Ranchin, Rolando Cimaz, Paula Romagnani, Christophe Malcus, Nicole FabienMarie-Nathalie Sarda, Behrouz Kassai, Jean Christophe Lega, Stephane Decramer, Pauline Abou-Jaoude, Ian Bruce, Thomas Simonet, Claire Bardel, Pierre Antoine Rollat-Farnier, Sébastien Viel, Héloïse Reumaux, James O'Sullivan, Thierry Walzer, Anne-Laure Mathieu, Gaëlle Marenne, Thomas Ludwig, Emmanuelle Genin, Jamie Ellingford, Brigitte Bader-Meunier, Tracy Briggs, Michael W Beresford, Yanick Crow

Research output: Contribution to journalArticlepeer-review


Background Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered
important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice,
while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of
rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE.
Methods For this genetic panel analysis we designed a next-generation sequencing panel comprising 147 genes,
including all known lupus-causing genes in humans, and potentially lupus-causing genes identified through
GWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteria
for SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these data
with those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREX
Findings After filtering, mendelian genotypes were confirmed in eight probands, involving variants in C1QA, C1QC,
C2, DNASE1L3, and IKZF1. Seven additional patients carried heterozygous variants in complement or type I
interferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9
recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in the
childhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified to
harbour at least one rare, predicted damaging variant (p=2·98 × 10−¹¹). Inborn errors of immunity were estimated
to account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the main
monogenic contribution.
Interpretation An accumulation of rare variants that are predicted to be damaging in SLE-associated genes might
contribute to disease expression and clinical heterogeneity.
Original languageEnglish
Pages (from-to)e99-109
Number of pages10
JournalThe Lancet Rheumatology
Early online date13 Jan 2020
Publication statusPublished - Feb 2020


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