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Journal Articles The Lancet Rheumatology Year : 2020

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 , Rangaraj Satyapal , Ethan Sen , Nick Wilkinson , Fiona Wood
1 Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases
2 Academic Unit of Medical Genetic
3 RDP - Reproduction et développement des plantes
4 IBS - UMR 5075 - Institut de biologie structurale
5 HCL - Hospices Civils de Lyon
6 LBMC - Laboratoire de Biologie Moléculaire de la Cellule
7 Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo
8 Developpement Normal et Pathologique du Système Immunitaire
9 Service de néphrologie, rhumatologie et dermatologie pédiatriques [Hôpital Femme Mère Enfant, HCL]
10 Rheumatology Unit, Department of Paediatrics
11 Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France
12 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
13 Evaluation et modélisation des effets thérapeutiques [LBBE]
14 I2MR - Institut de médecine moléculaire de Rangueil
15 University of Manchester [Manchester]
16 Unité Pédiatrique [Jeanne de Flandre]
17 Genetic Medicine
18 Spanish National Cancer Research Centre
19 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
20 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
21 Service d'immuno-hématologie pédiatrique [CHU Necker]
22 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
23 Service de neurologie [Rouen]
24 UB - Université de Bordeaux
25 CNG - Centre National de Génotypage
26 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
27 ITX - ITX - unité de recherche de l'institut du thorax
28 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
29 Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM]
30 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
31 CHU Saint-Antoine [AP-HP]
32 service pédiatrique de dialyse et de transplantation rénales
33 Service de médecine interne [Lille]
34 PPAV - "Personal Protection Against Vectors" working group
35 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
36 Hôpital Bicêtre
37 Service de Pédiatrie [Nancy]
38 Service de médecine interne
39 Paediatrics, Paediatric Internal Medicine, Rheumatology and Infectious Diseases [Paris]
40 Service de Pédiatrie Générale et Rhumatologie Pédiatrique
41 Service de rhumatologie [Strasbourg]
42 Service de Pédiatrie - Néphrologie, Médecine interne, Hypertension
43 Edin. - University of Edinburgh
Gillian Rice
  • Function : Author
  • PersonId : 932509
Sulliman Ommar Omarjee
  • Function : Author
Quentin Rouchon
  • Function : Author
Eve Smith
  • Function : Author
Marion Moreews
Maud Tusseau
  • Function : Author
Cécile Frachette
Nicole M. Thielens
Paula Romagnani
  • Function : Author
Marie-Nathalie Sarda
  • Function : Author
Jean-Christophe Lega
Pauline Abou-Jaoude
  • Function : Author
Ian Bruce
  • Function : Author
  • PersonId : 1049998
Claire Bardel
Pierre Antoine Rollat-Farnier
  • Function : Author
Gaëlle Marenne
Jamie Ellingford
  • Function : Author
Michael Beresford
  • Function : Author
Yanick Crow
Dominique Campion
  • Function : Author
  • PersonId : 863253
Jean-François Dartigues
  • Function : Author
  • PersonId : 842748
Jean-François Deleuze
  • Function : Author
  • PersonId : 1015006
Kenza Bouayed
  • Function : Author
Olivier Fain
Eric Hachulla
Isabelle Kone-Paut
  • Function : Author
  • PersonId : 947672
Irène Lemelle
Eslam Al-Abadi
  • Function : Author
Kate Armon
  • Function : Author
Kathryn Bailey
  • Function : Author
Coziana Ciurtin
  • Function : Author
Janet Gardner-Medwin
  • Function : Author
Kirsty Haslam
  • Function : Author
Daniel Hawley
  • Function : Author
Alice Leahy
  • Function : Author
Valentina Leone
  • Function : Author
Devesh Mewar
  • Function : Author
Rob Moots
  • Function : Author
Clarissa Pilkington
  • Function : Author
Athimalaipet Ramanan
  • Function : Author
Annie Ratcliffe
  • Function : Author
Arani Sridhar
  • Function : Author
Philip Riley
  • Function : Author
  • PersonId : 831006
Rangaraj Satyapal
  • Function : Author
Ethan Sen
  • Function : Author
Nick Wilkinson
  • Function : Author
Fiona Wood
  • Function : Author

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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Dates and versions

hal-02867795 , version 1 (08-04-2024)

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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, 2020, 2 (2), pp.e99-e109. ⟨10.1016/S2665-9913(19)30142-0⟩. ⟨hal-02867795⟩
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