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

被引：57

作者：

Belot, Alexandre ^{[1
,2
]}

Rice, Gillian, I ^{[3
]}

Omarjee, Sulloman Ommar ^{[2
]}

Rouchon, Quentin ^{[4
,5
]}

Smith, Eve M. D. ^{[6
,7
]}

Moreews, Marion ^{[2
]}

Tusseau, Maud ^{[2
]}

Frachette, Cecile ^{[1
,2
]}

Bournhonesque, Raphael ^{[2
]}

Thielens, Nicole ^{[8
]}

Gaboriaud, Christine ^{[8
]}

Rouvet, Isabelle ^{[9
]}

Chopin, Emilie ^{[9
]}

Hoshino, Akihiro ^{[10
]}

Latour, Sylvain ^{[10
,11
]}

Ranchin, Bruno ^{[1
]}

Cimaz, Rolando ^{[12
,13
]}

Romagnani, Paula ^{[13
,14
]}

Malcus, Christophe ^{[15
]}

Fabien, Nicole ^{[16
]}

Sarda, Marie-Nathafie ^{[16
]}

Kassai, Behrouz ^{[17
,18
]}

Lega, Jean-Christophe ^{[19
]}

Decramer, Stephan ^{[20
,21
,22
]}

Abou-Jaoude, Pauline ^{[23
]}

Bruce, Ian N. ^{[24
,25
]}

Simonet, Thomas ^{[26
]}

Bardel, Claire ^{[26
,27
]}

Rollat-Farrier, Pierre Antoine ^{[27
]}

Viel, Sebastien ^{[16
]}

Reumaux, Heloise ^{[28
]}

O'Sullivan, James ^{[29
]}

Waizer, Thierry ^{[2
]}

Mathieu, Anne-Laure ^{[2
]}

Marenne, Gaelie ^{[30
]}

Ludwig, Thomas ^{[30
,31
]}

Genin, Emmanuelle ^{[30
]}

Ellingford, Jamie ^{[29
]}

Bader-Meunier, Brigitte ^{[32
]}

Briggs, Tracy A. ^{[3
,29
]}

Beresford, Michael W. ^{[6
,7
]}

Crow, Yanick J. ^{[33
,34
,35
]}

机构：

[1] Hosp Civils Lyon, Femme Mere Enfant Hosp, Dermatol Unit, Paediat Nephrol,Rheumatol, Lyon, France

[2] Univ Lyon 1, CNRS, UMR5308,CIRI, Ecole Normale Super Lyon,Inserm,Int Ctr Infectiol, Lyon, France

[3] Univ Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Div Evolut & Genom Sci, Manchester, Lancs, England

[4] VIB Ctr Inflammat Res, Data Min & Modelling Biomed, Ghent, Belgium

[5] Univ Ghent, Dept Appl Math Comp Sci & Stat, Ghent, Belgium

[6] Alder Hey Childrens NHS Fdn Trust, Paediat Rheumatol, Liverpool, Merseyside, England

[7] Univ Liverpool, Inst Translat Med, Dept Women & Childrens Hlth, Liverpool, Merseyside, England

[8] Univ Grenoble Alpes, CNRS, CEA, IBS, F-38000 Grenoble, France

[9] Hosp Civils Lyon, Grp Hosp Est, Ctr Biotechnol Cellulaire & Biotheque, F-69677 Bron, France

[10] INSERM UMR 1163, Lab Lymphocyte Activat & Susceptibil EBV Infect, Paris, France

[11] Univ Paris 05, Sorbonne Paris Cite, Imagine Inst, Paris, France

[12] Anna Meyer Children Hosp, Rheumatol Unit, Florence, Italy

[13] Univ Florence, Florence, Italy

[14] Anna Meyer Children Hosp, Nephrol Unit, Florence, Italy

[15] Hospkes Civils Lyon, Hop Edouard Herriot, Serv Immunol, F-69437 Lyon, France

[16] CHLS, Hosp Civils Lyon, Serv Immunol, F-69495 Pierre Benite, France

[17] Hosp Civils Lyon, Serv Pharmacotoxicol, INSERM, EPICIME CIC 1407 Lyon, F-69677 Bron, France

[18] Univ Lyon 1, F-69677 Bron, France

[19] Univ Lyon 1, Pierre Benite, Hosp Civils Lyon, Internal Med Unit,CHLS, Lyon, France

[20] CHU Toulouse, Dept Pediat Nephrol, Toulouse, France

[21] Reference Malad Renales Rares Sud Ouest, Toulouse, France

[22] Inserm U1048, Toulouse, France

[23] Univ Med Ctr, St George Hosp, Dept Paediat Nephrol, Beirut, Lebanon

[24] Univ Manchester, Sch Biol Sci, Ctr Musculoskeletal Res, Div Musculoskeletal & Dermatol Sci, Manchester, Lancs, England

[25] Univ Manchester, Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, NIHR Manchester Biomed Res Ctr, Manchester, Lancs, England

[26] Hosp Civils Lyon, Dept Biostat Bioinformat, F-69677 Bron, France

[27] Lyon 1 Univ, Lyon Univ, Biometry & Evolutionary Biol Lab, CNRS UMRS558, F-69622 Villeurbanne, France

[28] CHU Lille, Pediat Rheumatol Unit, F-59000 Lille, France

[29] Manchester Univ NHS Fdn Trust, St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, Manchester, Lancs, England

[30] Univ Brest, INSERM, EFS, UMR 1078,GGB, F-29200 Brest, France

[31] CHU Brest, Brest, France

[32] Hop Necker Enfants Malad, Imagine Inst, Paediat Rheumatol & Immunol Unit, Paris, France

[33] Inst Imagine, Lab Neurogenet & Neuroinflammat, Paris, France

[34] Paris Descartes Univ, Inst Imagine, Sorbonne Paris Cite, Paris, France

[35] Univ Edinburgh, Ctr Genom & Expt Med, MK Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

来源：

LANCET RHEUMATOLOGY | 2020年 / 2卷 / 02期

基金：

欧洲研究理事会; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

MUTATIONS; ERYTHEMATOSUS; DISEASE; ASSOCIATION; DEFICIENCY; IMPLICATE; TREX1;

D O I：

10.1016/S2665-9913(19)30142-0

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 1KZF1, Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosoinal 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 x10(-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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

引用

页码：E99 / E109

页数：11

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