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).