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 Fabien; Marie-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

doi:10.1016/S2665-9913(19)30142-0

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

University of Florence

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	e99-109
Number of pages	10
Journal	The Lancet Rheumatology
Volume	2
Early online date	13 Jan 2020
DOIs	https://doi.org/10.1016/S2665-9913(19)30142-0
Publication status	Published - Feb 2020

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10.1016/S2665-9913(19)30142-0

A Prospective Natural History Study to Enhance Understanding of the Phenotypes Associated with Type I Interferonopathies and the Lupus Extended Phenotype Study.
Briggs, T. (PI)
1/11/18 → 30/04/22
Project: Research

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Belot, A., Rice, G., Ommar, O. S., Rouchon, Q., Smith, E. M. D., Moreews, M., Tusseau, M., Frachette, C., Bournhonesque, R., Thielens, N., Gaboriaud, C., Rouvet, I., Chopin, E., Hoshino, A., Latour, S., Ranchin, B., Cimaz, R., Romagnani, P., Malcus, C., ... Crow, Y. (2020). 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, 2, e99-109. https://doi.org/10.1016/S2665-9913(19)30142-0

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

abstract = "SummaryBackground Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are consideredimportant 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 ofrare 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 throughGWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteriafor SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these datawith those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREXConsortium.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 Iinterferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in thechildhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified toharbour at least one rare, predicted damaging variant (p=2·98 × 10−¹¹). Inborn errors of immunity were estimatedto account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the mainmonogenic contribution.Interpretation An accumulation of rare variants that are predicted to be damaging in SLE-associated genes mightcontribute to disease expression and clinical heterogeneity.",

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

year = "2020",

month = feb,

doi = "10.1016/S2665-9913(19)30142-0",

language = "English",

volume = "2",

pages = "e99--109",

journal = "The Lancet Rheumatology",

issn = "2665-9913",

publisher = "Elsevier BV",

}

Belot, A, Rice, G, Ommar, OS, Rouchon, Q, Smith, EMD, Moreews, M, Tusseau, M, Frachette, C, Bournhonesque, R, Thielens, N, Gaboriaud, C, Rouvet, I, Chopin, E, Hoshino, A, Latour, S, Ranchin, B, Cimaz, R, Romagnani, P, Malcus, C, Fabien, N, Sarda, M-N, Kassai, B, Lega, JC, Decramer, S, Abou-Jaoude, P, Bruce, I, Simonet, T, Bardel, C, Rollat-Farnier, PA, Viel, S, Reumaux, H, O'Sullivan, J, Walzer, T, Mathieu, A-L, Marenne, G, Ludwig, T, Genin, E, Ellingford, J, Bader-Meunier, B, Briggs, T, Beresford, MW & Crow, Y 2020, '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, vol. 2, pp. e99-109. https://doi.org/10.1016/S2665-9913(19)30142-0

TY - JOUR

T1 - Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts

AU - Belot, Alexandre

AU - Rice, Gillian

AU - Ommar, Omarjee Sulliman

AU - Rouchon, Quentin

AU - Smith, Eve M D

AU - Moreews, Marion

AU - Tusseau, Maud

AU - Frachette, Cecile

AU - Bournhonesque, Raphael

AU - Thielens, Nicole

AU - Gaboriaud, Christine

AU - Rouvet, Isabelle

AU - Chopin, Emilie

AU - Hoshino, Akihiro

AU - Latour, Sylvain

AU - Ranchin, Bruno

AU - Cimaz, Rolando

AU - Romagnani, Paula

AU - Malcus, Christophe

AU - Fabien, Nicole

AU - Sarda, Marie-Nathalie

AU - Kassai, Behrouz

AU - Lega, Jean Christophe

AU - Decramer, Stephane

AU - Abou-Jaoude, Pauline

AU - Bruce, Ian

AU - Simonet, Thomas

AU - Bardel, Claire

AU - Rollat-Farnier, Pierre Antoine

AU - Viel, Sébastien

AU - Reumaux, Héloïse

AU - O'Sullivan, James

AU - Walzer, Thierry

AU - Mathieu, Anne-Laure

AU - Marenne, Gaëlle

AU - Ludwig, Thomas

AU - Genin, Emmanuelle

AU - Ellingford, Jamie

AU - Bader-Meunier, Brigitte

AU - Briggs, Tracy

AU - Beresford, Michael W

AU - Crow, Yanick

PY - 2020/2

Y1 - 2020/2

N2 - SummaryBackground Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are consideredimportant 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 ofrare 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 throughGWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteriafor SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these datawith those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREXConsortium.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 Iinterferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in thechildhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified toharbour at least one rare, predicted damaging variant (p=2·98 × 10−¹¹). Inborn errors of immunity were estimatedto account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the mainmonogenic contribution.Interpretation An accumulation of rare variants that are predicted to be damaging in SLE-associated genes mightcontribute to disease expression and clinical heterogeneity.

AB - SummaryBackground Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are consideredimportant 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 ofrare 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 throughGWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteriafor SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these datawith those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREXConsortium.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 Iinterferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in thechildhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified toharbour at least one rare, predicted damaging variant (p=2·98 × 10−¹¹). Inborn errors of immunity were estimatedto account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the mainmonogenic contribution.Interpretation An accumulation of rare variants that are predicted to be damaging in SLE-associated genes mightcontribute to disease expression and clinical heterogeneity.

U2 - 10.1016/S2665-9913(19)30142-0

DO - 10.1016/S2665-9913(19)30142-0

M3 - Article

SN - 2665-9913

VL - 2

SP - e99-109

JO - The Lancet Rheumatology

JF - The Lancet Rheumatology

ER -

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

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A Prospective Natural History Study to Enhance Understanding of the Phenotypes Associated with Type I Interferonopathies and the Lupus Extended Phenotype Study.

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