Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts
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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DOI：
10.1016/s2665-9913(19)30142-0
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发表时间：
2020-02-01
影响因子：
25.4
通讯作者：
Crow, Yanick J.
中科院分区：
文献类型：
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作者：
Belot, Alexandre;Rice, Gillian, I;Crow, Yanick J.
背景系统性红斑狼疮（SLE）是一种罕见的免疫系统疾病，遗传因素被认为是其发病的重要因素。单基因狼疮在人类中与大约30种基因型相关，在小鼠中与60种基因型相关，而全基因组关联研究已经确定了90多个风险位点。我们的目的是分析罕见的和预测的致病基因变异的贡献在一个人口中的儿童期发病sleep.Methods的病例，我们设计了一个新一代的测序面板，包括147个基因，包括所有已知的狼疮引起的基因在人类，并可能通过GWAS和动物模型确定的狼疮引起的基因。我们筛选了117名符合美国流变学学会（ACR）SLE标准的先证者，通过英国和法国儿童期发病SLE队列确定，并将这些数据与来自1000个基因组计划的791名种族匹配对照和来自FREX Consortium的574名对照进行比较。C2、DNASE 1 L3和1 KZF 1，另外7名患者携带补体或I型干扰素相关的自体隐性基因的杂合变体，其中2名患者的编码蛋白C3和C9浓度降低。与对照组相比，在儿童期发病的SLE队列中，被预测为损害性的罕见变异显著富集; 25%的SLE先证者与5%的对照组被确定为至少携带一种罕见的、预测的损害性变异（p=2-98 x10（-11））。据估计，先天性免疫缺陷占儿童期发病的SLE病例的7%，其中先天免疫缺陷是主要的单基因贡献。解释预计对SLE相关基因具有破坏性的罕见变异的积累可能会导致疾病表现和临床异质性。版权所有（C）2020爱思唯尔有限公司保留所有权利。
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 1KZF1, Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosoinal 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 x10(-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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.