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

Alexandre Belot 1 Gillian Rice 2 Sulliman Ommar Omarjee Quentin Rouchon Eve Smith Marion Moreews Maud Tusseau Cécile Frachette Raphael Bournhonesque 3 Nicole M. Thielens 4 Christine Gaboriaud 4 Isabelle Rouvet 5 Emilie Chopin 6 Akihiro Hoshino 7 Sylvain Latour 8 Bruno Ranchin 9 Rolando Cimaz 10 Paula Romagnani Christophe Malcus 11 Nicole Fabien 12 Marie-Nathalie Sarda Behrouz Kassai 13 Jean-Christophe Lega 5 Stéphane Decramer 14 Pauline Abou-Jaoude Ian Bruce 15 Thomas Simonet 6 Claire Bardel Pierre Antoine Rollat-Farnier Sébastien Viel 1 Héloïse Reumaux 16 James O'Sullivan 17 Thierry Walzer 1 Anne-Laure Mathieu 1 Gaëlle Marenne 18 Thomas Ludwig 19 Emmanuelle Génin 20 Jamie Ellingford Brigitte Bader-Meunier 21 Tracy Briggs 15 Michael Beresford Yanick Crow 22 Dominique Campion 23 Jean-François Dartigues 24 Jean-François Deleuze 25 Jean-Charles Lambert 26 Richard Redon 27 Emma Allain-Launay 28 Kenza Bouayed Stéphane Burtey 29 Véronique Despert 30 Olivier Fain 31 Michel Fischbach 32 Eric Hachulla 33 Yves Hatchuel 34 Jean-François Kleinmann 35 Isabelle Kone-Paut 36 Irène Lemelle 37 François Maurier 38 Ulrich Meinzer 39 Isabelle Melki 22 Maryam Piram 40 Jean Sibilia 41 Olivia Weill 42 Eslam Al-Abadi Kate Armon Kathryn Bailey Mary Brennan 43 Coziana Ciurtin Janet Gardner-Medwin Kirsty Haslam Daniel Hawley Alice Leahy Valentina Leone Devesh Mewar Rob Moots Clarissa Pilkington Athimalaipet Ramanan Annie Ratcliffe Arani Sridhar Philip Riley 44 Rangaraj Satyapal Ethan Sen Nick Wilkinson Fiona Wood 
13 Evaluation et modélisation des effets thérapeutiques
Département biostatistiques et modélisation pour la santé et l'environnement [LBBE]
Abstract : 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 Consortium. 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.
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Submitted on : Monday, June 15, 2020 - 9:05:30 AM
Last modification on : Friday, September 30, 2022 - 12:00:07 PM

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Alexandre Belot, Gillian Rice, Sulliman Ommar Omarjee, Quentin Rouchon, Eve Smith, et al.. Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts. The Lancet Rheumatology, Elsevier, 2020, 2 (2), pp.e99-e109. ⟨10.1016/S2665-9913(19)30142-0⟩. ⟨hal-02867795⟩



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