Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE

被引：28

作者：

Charras, Amandine ^{[1
]}

Haldenby, Sam ^{[2
]}

Smith, Eve M. D. ^{[1
,3
]}

Egbivwie, Naomi ^{[1
,3
]}

Olohan, Lisa ^{[2
]}

Kenny, John G. ^{[2
,4
]}

Schwarz, Klaus ^{[5
,6
]}

Roberts, Carla ^{[1
]}

Al-Abadi, Eslam ^{[7
]}

Armon, Kate ^{[8
]}

Bailey, Kathryn ^{[9
]}

Ciurtin, Coziana ^{[10
]}

Gardner-Medwin, Janet ^{[11
]}

Haslam, Kirsty ^{[12
]}

Hawley, Daniel P. ^{[13
]}

Leahy, Alice ^{[14
]}

Leone, Valentina ^{[15
]}

McErlane, Flora ^{[16
]}

Modgil, Gita ^{[17
]}

Pilkington, Clarissa ^{[18
]}

Ramanan, Athimalaipet, V ^{[19
,20
]}

Rangaraj, Satyapal ^{[21
]}

Riley, Phil ^{[22
]}

Sridhar, Arani ^{[23
]}

Beresford, Michael W. ^{[1
,2
]}

Hedrich, Christian M. ^{[1
,2
]}

机构：

[1] Univ Liverpool, Inst Life Course & Med Sci, Dept Womens & Childrens Hlth, Liverpool, Merseyside, England

[2] Univ Liverpool, Ctr Genom Res, Inst Infect Vet & Ecol Sci, Liverpool, Merseyside, England

[3] Alder Hey Childrens NHS Fdn Trust Hosp, Dept Paediat Rheumatol, Liverpool, Merseyside, England

[4] TEAGASC, Food Res Ctr, Moorepk, Cork, Ireland

[5] Univ Ulm, Inst Transfus Med, Ulm, Germany

[6] German Red Cross Blood Serv Baden Wurttemberg Hes, Inst Clin Transfus Med & Immunogenet Ulm, Ulm, Germany

[7] Birmingham Childrens Hosp, Dept Rheumatol, Birmingham, W Midlands, England

[8] Cambridge Univ Hosp, Dept Paediat Rheumatol, Cambridge, England

[9] Oxford Univ Hosp NHS Fdn Trust, Dept Paediat Rheumatol, Oxford, England

[10] UCL, Ctr Adolescent Rheumatol, London, England

[11] Univ Glasgow, Dept Child Hlth, Glasgow, Lanark, Scotland

[12] Bradford Royal Infirm, Dept Paediat, Bradford, W Yorkshire, England

[13] Sheffield Childrens Hosp, Dept Paediat Rheumatol, Sheffield, S Yorkshire, England

[14] Southampton Gen Hosp, Dept Paediat Rheumatol, Southampton, Hants, England

[15] Leeds Children Hosp, Dept Paediat Rheumatol, Leeds, W Yorkshire, England

[16] Newcastle Univ, Great North Childrens Hosp, Royal Victoria Infirm, Inst Cellular Med,Paediat Rheumatol, Newcastle Upon Tyne, Tyne & Wear, England

[17] Musgrove Pk Hosp, Dept Paediat, Taunton, Somerset, England

[18] Great Ormond St Hosp Sick Children, Dept Paediat Rheumatol, London, England

[19] Univ Hosp Bristol NHS Fdn Trust, Bristol, Avon, England

[20] Univ Bristol, Bristol Med Sch, Bristol, Avon, England

[21] Nottingham Univ Hosp, Dept Paediat Rheumatol, Nottingham, England

[22] Royal Manchester Childrens Hosp, Dept Paediat Rheumatol, Manchester, Lancs, England

[23] Leicester Royal Infirm, Dept Paediat, Leicester, Leics, England

来源：

RHEUMATOLOGY | 2023年 / 62卷 / SI2期

基金：

英国医学研究理事会;

关键词：

SLE; juvenile-onset; paediatric; childhood; !text type='jS']jS[!/text]LE; genetic; monogenic; stratification; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CLASSIFICATION CRITERIA; DISEASE; SAMHD1; POLYMORPHISMS; DEFICIENCY; MUTATIONS; RNASEH2A; TREX1; RISK;

D O I：

10.1093/rheumatology/keac275

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objectives 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. Methods 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. Results Damaging gene variants were identified in similar to 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. Conclusion 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.

引用

页码：SI210 / SI225

页数：16

共 48 条

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