Exome sequencing enables molecular diagnosis in 10% of early-onset or familial systemic lupus erythematosus cases

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, multi-organ autoimmune disease characterised by a highly heterogeneous presentation. Specific genetic variations predispose patients to the disease, and rare monogenic forms caused by single-gene variations have been identified in a small percentage of patients, often with early disease onset. In this study, we used exome sequencing in a large cohort of patient with juvenile-onset SLE to gain insight into the genetic basis of juvenile SLE (jSLE). METHODS: Patients were selected if disease onset occurred before the age of 18. We performed exome sequencing on 263 individuals across 172 distinct families. The majority of cases were solo exomes (n = 118), while others included affected duos, trios, or multiplex families (n = 18 + 5 + 1), as well as classical trios with unaffected parents (n = 30). FINDINGS: A molecular diagnosis consistent with the clinical presentation was established in 17 patients from unrelated families (10%). Among them, we identified pathogenic or likely pathogenic variants in genes previously associated with monogenic lupus, including a novel C1QA variant as well as other lupus-associated genes (COPA, ADAR, TLR7, IKZF3, RELA, PTPN11, SERPING1). Strikingly, exome sequencing also revealed variants in immunodeficiency-associated genes (IRAK4, USB1), autoinflammatory disorders (PSTPIP1) and unexpected candidates like ETV6, and MAN1B1 revealing previously unrecognised pathways in SLE development. Syndromic features and very early-onset (before the age of 5) were strongly associated with a higher diagnostic yield, reaching nearly 33% in these subgroups. INTERPRETATION: This study expands our understanding of causes of lupus, highlighting its genetic heterogeneity. It also supports the systematic use of genetic testing in cases of juvenile lupus, especially those with very early onset or syndromic features, regardless of the clinical presentation. Given the range of unexpected molecular diagnoses identified in this study, pangenomic analysis such as exome or genome sequencing appears to be the most appropriate approach in these cases. FUNDING: This work was supported by: The Institut National de la Santé et de la Recherche Médicale (INSERM); Government grants managed by the Agence Nationale de la Recherche (ANR) as part of the "Investment for the Future" program: Institut Hospitalo-Universitaire Imagine (ANR-10-IAHU-01), Recherche Hospitalo-Universitaire (ANR-18-RHUS-0010); The Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH); The Fondation pour la Recherche Médicale (FRM: EQU202103012670, FDM202006011291); French and European grants managed by the ANR: ANR-14-CE14-0026 (Lumugène), ANR-21-CE17-0064 (SOCSIMMUNITY); The National Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE).

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Journal
EBioMedicine
Published
2026-04-01
DOI
https://doi.org/10.1016/j.ebiom.2026.106209
Primary Topic
Systemic Lupus Erythematosus Research
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article
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article

Exome sequencing enables molecular diagnosis in 10% of early-onset or familial systemic lupus erythematosus cases

Isabelle Pellier, Florence A. Aeschlimann, Fitsum Guebre-Egziabher, Florence Uettwiller et al.
EBioMedicine
Systemic Lupus Erythematosus Research
article

Exome sequencing enables molecular diagnosis in 10% of early-onset or familial systemic lupus erythematosus cases

Isabelle Pellier, Florence A. Aeschlimann, Fitsum Guebre-Egziabher, Florence Uettwiller, Bilade Cherqaoui, David Gonçalves, Iona Madden, Nicolas Pottier, Martin Killian, F. Sarrot-Reynauld, I. Durieu, Perrine Dusser-Benesty, Quentin Riller, Férielle Louillet, Jérôme Harambat, Diego Urbina, K. Retornaz, Catherine Didailler, Lise Allard, I. Lemelle, Samira Khaldi-Plassart, Corentin Molitor, Christine Gaboriaud, Wadih Abou Chahla, Marine Fouillet-Desjonquères, Camille Faudeux, Antoine Briantais, Tomohiro Morio, Alexandra Cambier, Pierre Quartier dit Maire, Gaëtan Lesca, N. Le Gouellec, A. Welfringer-Morin, D. Sanlaville, Nicole M. Thielens, Héloïse Reumaux, Motoi Yamashita, Thomas Simonet, Thierry Walzer, Sébastien Viel, Capucine Pïcard, Yves Hatchuel, Philippe Guilpain, Karine Brochard-Payet, Éloïse Colliou, Audrey Laurent, Isabelle Rouvet, Stéphane Decramer, L. Besson-Leaud, Wassila Messadi, Emilie Chopin, Franck Zekre, Olivia Boyer, Hugues Flodrops, Nicole Fabien, Dirk Holzinger, Maud Tusseau, Vincent Guigonis, Claire Ballot, Guylhène Bourdat, Romain Larrue, Antoine Mouche, E. Ghrenassia, Brigitte Bader-Meunier, Adrien Subervie, Ulrich Meinzer, Jean‐François Viallard, Audrey Labalme, Pascal Pillet, V. Despert, Lionel Heiser, Aurélia Carbasse, Carine El-Sissy, Maurine Jouret, Raju P Khubchandani, Frédéric Rieux-Laucat, Jean-Christophe LEGA, B. Ranchin, Véronique Fremeaux-Bacchi, Isabelle Kone-Paut, Isabelle Melki, Arsène Mekinian, Eric Hachulla, Alice de Pellegars Malhortie, Rose-Marie Herbigneaux, Hazem Manadile, Charlotte Kevorkian-Verguet, Alexandre Belot, Stéphane Burtey, Olivier Dunard, Caroline Rousset-Rouvière, Soizic Tiriau, Anne-Laure Mathieu, Mélanie Blin, Christophe Richez, Linda Rossi, Olivier Richer, Anne-Sophie Parentelli, François Maurier, Sandrine Morell-Dubois
article en

Abstract

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, multi-organ autoimmune disease characterised by a highly heterogeneous presentation. Specific genetic variations predispose patients to the disease, and rare monogenic forms caused by single-gene variations have been identified in a small percentage of patients, often with early disease onset. In this study, we used exome sequencing in a large cohort of patient with juvenile-onset SLE to gain insight into the genetic basis of juvenile SLE (jSLE). METHODS: Patients were selected if disease onset occurred before the age of 18. We performed exome sequencing on 263 individuals across 172 distinct families. The majority of cases were solo exomes (n = 118), while others included affected duos, trios, or multiplex families (n = 18 + 5 + 1), as well as classical trios with unaffected parents (n = 30). FINDINGS: A molecular diagnosis consistent with the clinical presentation was established in 17 patients from unrelated families (10%). Among them, we identified pathogenic or likely pathogenic variants in genes previously associated with monogenic lupus, including a novel C1QA variant as well as other lupus-associated genes (COPA, ADAR, TLR7, IKZF3, RELA, PTPN11, SERPING1). Strikingly, exome sequencing also revealed variants in immunodeficiency-associated genes (IRAK4, USB1), autoinflammatory disorders (PSTPIP1) and unexpected candidates like ETV6, and MAN1B1 revealing previously unrecognised pathways in SLE development. Syndromic features and very early-onset (before the age of 5) were strongly associated with a higher diagnostic yield, reaching nearly 33% in these subgroups. INTERPRETATION: This study expands our understanding of causes of lupus, highlighting its genetic heterogeneity. It also supports the systematic use of genetic testing in cases of juvenile lupus, especially those with very early onset or syndromic features, regardless of the clinical presentation. Given the range of unexpected molecular diagnoses identified in this study, pangenomic analysis such as exome or genome sequencing appears to be the most appropriate approach in these cases. FUNDING: This work was supported by: The Institut National de la Santé et de la Recherche Médicale (INSERM); Government grants managed by the Agence Nationale de la Recherche (ANR) as part of the "Investment for the Future" program: Institut Hospitalo-Universitaire Imagine (ANR-10-IAHU-01), Recherche Hospitalo-Universitaire (ANR-18-RHUS-0010); The Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH); The Fondation pour la Recherche Médicale (FRM: EQU202103012670, FDM202006011291); French and European grants managed by the ANR: ANR-14-CE14-0026 (Lumugène), ANR-21-CE17-0064 (SOCSIMMUNITY); The National Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE).

EBioMedicineVol. 126
Université Claude Bernard Lyon 1 (FR), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), Inserm (FR), Lyon College (US), University of Algiers Benyoucef Benkhedda (DZ), Université Paris Cité (FR), Université de Lille (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Centre Hospitalier Universitaire de Grenoble (FR), Institut Pasteur de Lille (FR), Centre Hospitalier Universitaire de Lille (FR), CEA Grenoble (FR), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), Centre Hospitalier Universitaire de Besançon (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre de Référence des Maladies Autoinflammatoires et des Amyloses (FR), Hospices Civils de Lyon (FR), Laboratoire de Biologie et Modélisation de la Cellule (FR), Hôpital Européen Georges-Pompidou (FR), Hôpital Saint-Antoine (FR), Hôpital Jeanne de Flandre (FR), Hôpital Pellegrin (FR), Hôpital Lyon Sud (FR), Hôpital Privé Jean Mermo (FR), Centre de Recherche Saint-Antoine (FR), Centre Hospitalier Universitaire de Martinique (MQ), RIKEN Center for Integrative Medical Sciences (JP), Institut de Biologie Structurale (FR), Centre International de Recherche en Infectiologie (FR), Bicêtre Hospital (FR), Institut des Maladies Génétiques Imagine (FR), Université de Rouen Normandie (FR), Advanced Institute of Industrial Technology (JP), Université Grenoble Alpes (FR)
Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale
Good health and well-being
Openalex Percentile: Top 36%
Systemic Lupus Erythematosus Research
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