作者
Alexandre Bélot,Gillian I. Rice,Ommar Omarjee,Quentin Rouchon,Eve Smith,Marion Moreews,Maud Tusseau,Cécile Frachette,Raphael Bournhonesque,Nicole M. Thielens,Christine Gaboriaud,Isabelle Rouvet,Emilie Chopin,Akihiro Hoshino,Sylvain Latour,Bruno Ranchin,Rolando Cimaz,Paula Romagnani,Christophe Malcus,Nicole Fabien,Marie-Nathalie Kolopp Sarda,Behrouz Kassaï,Jean‐Christophe Lega,Stéphane Decramer,Pauline Abou-Jaoude,Ian N. 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 Génin,Jamie M Ellingford,Brigitte Bader‐Meunier,Tracy A Briggs,Michael W. Beresford,Yanick J. Crow,Dominique Campion,Jean‐François Dartigues,Jean‐François Deleuze,Emmanuelle Génin,Jean‐Charles Lambert,Richard Redon,Emma Allain-Launay,Brigitte Bader‐Meunier,Alexandre Bélot,Kenza Bouayed,Stéphane Burtey,Aurélia Carbasse,Stéphane Decramer,Véronique Despert,Olivier Fain,Michel Fischbach,Hugues Flodrops,Caroline Galeotti,É. Hachulla,Yves Hatchuel,J.F. Kleinmann,Isabelle Koné‐Paut,Aurélia Lanteri,I. Lemelle,Hélène Maillard,F. Maurier,Ulrich Meinzer,Isabelle Melki,Sandrine Morell-Dubois,Anne Pagnier,Maryam Piram,Bruno Ranchin,Héloïse Reumaux,Charlotte Samaille,Jean Sibilia,Olivia Weill,Eslam Al‐Abadi,Kate Armon,Kathryn Bailey,Michael W. Beresford,Mary Brennan,Coziana Ciurtin,Janet Gardner‐Medwin,Kirsty Haslam,Daniel Hawley,Alice Leahy,Valentina Leone,Devesh Mewar,Rob Moots,Clarissa Pilkington,Athimalaipet V Ramanan,Satyapal Rangaraj,Annie Ratcliffe,Philip Riley,Ethan S Sen,Arani Sridhar,Nick Wilkinson,Fiona Wood
摘要
Summary
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. Funding
European Research Council.