Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE.
SLE
childhood
genetic
jSLE
juvenile-onset
monogenic
paediatric
stratification
Journal
Rheumatology (Oxford, England)
ISSN: 1462-0332
Titre abrégé: Rheumatology (Oxford)
Pays: England
ID NLM: 100883501
Informations de publication
Date de publication:
23 02 2023
23 02 2023
Historique:
received:
20
10
2021
revised:
22
04
2022
pubmed:
10
5
2022
medline:
3
3
2023
entrez:
9
5
2022
Statut:
ppublish
Résumé
Juvenile-onset systemic lupus erythematosus (jSLE) affects 15-20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with 'genetic' SLE vs remaining SLE patients. Based on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets. Damaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, 'genetic' SLE affected younger children and more Black African/Caribbean patients. 'Genetic' SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in 'genetic' SLE patients, but more second and third line agents were used. 'Genetic' SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit. Approximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in 'genetic' SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity.
Identifiants
pubmed: 35532072
pii: 6582551
doi: 10.1093/rheumatology/keac275
pmc: PMC9949710
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
SI210-SI225Subventions
Organisme : Medical Research Council
ID : MR/R013926/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.
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