Abstract：
Genetics play an important role in systemic lupus erythematosus (SLE) pathogenesis. We calculated the prevalence of rare variants in known monogenic lupus genes among children suspected of monogenic lupus.
We completed paired-end genome-wide sequencing (whole genome sequencing [WGS] or whole exome sequencing) in patients suspected of monogenic lupus, and focused on 36 monogenic lupus genes. We prioritized rare (minor allele frequency < 1%) exonic, nonsynonymous, and splice variants with predicted pathogenicity classified as deleterious variants (Combined Annotation Dependent Depletion [CADD], PolyPhen2, and Sorting Intolerant From Tolerant [SIFT] scores). Additional filtering restricted to predicted damaging variants by considering reported zygosity. In those with WGS (n = 69), we examined copy number variants (CNVs) > 1 kb in size. We created additive non-HLA and HLA SLE genetic risk scores (GRSs) using common SLE-risk single-nucleotide polymorphisms. We tested the relationship between SLE GRSs and the number of rare variants with multivariate logistic models, adjusted for sex, ancestry, and age of diagnosis.
The cohort included 71 patients, 80% female, with a mean age at diagnosis of 8.9 (SD 3.2) years. We identified predicted damaging variants in 9 (13%) patients who were significantly younger at diagnosis compared to those without a predicted damaging variant (6.8 [SD 2.1] years vs 9.2 [SD 3.2] years, P = 0.01). We did not identify damaging CNVs. There was no significant association between non-HLA or HLA SLE GRSs and the odds of carrying ≥ 1 rare variant in multivariate analyses.
In a cohort of patients with suspected monogenic lupus who underwent genome-wide sequencing, 13% carried rare predicted damaging variants for monogenic lupus. Additional studies are needed to validate our findings.
We completed paired-end genome-wide sequencing (whole genome sequencing [WGS] or whole exome sequencing) in patients suspected of monogenic lupus, and focused on 36 monogenic lupus genes. We prioritized rare (minor allele frequency < 1%) exonic, nonsynonymous, and splice variants with predicted pathogenicity classified as deleterious variants (Combined Annotation Dependent Depletion [CADD], PolyPhen2, and Sorting Intolerant From Tolerant [SIFT] scores). Additional filtering restricted to predicted damaging variants by considering reported zygosity. In those with WGS (n = 69), we examined copy number variants (CNVs) > 1 kb in size. We created additive non-HLA and HLA SLE genetic risk scores (GRSs) using common SLE-risk single-nucleotide polymorphisms. We tested the relationship between SLE GRSs and the number of rare variants with multivariate logistic models, adjusted for sex, ancestry, and age of diagnosis.
The cohort included 71 patients, 80% female, with a mean age at diagnosis of 8.9 (SD 3.2) years. We identified predicted damaging variants in 9 (13%) patients who were significantly younger at diagnosis compared to those without a predicted damaging variant (6.8 [SD 2.1] years vs 9.2 [SD 3.2] years, P = 0.01). We did not identify damaging CNVs. There was no significant association between non-HLA or HLA SLE GRSs and the odds of carrying ≥ 1 rare variant in multivariate analyses.
In a cohort of patients with suspected monogenic lupus who underwent genome-wide sequencing, 13% carried rare predicted damaging variants for monogenic lupus. Additional studies are needed to validate our findings.
摘要：
目的：遗传学在系统性红斑狼疮（SLE）发病机制中起重要作用。我们计算了疑似单基因狼疮的儿童中已知单基因狼疮基因中罕见变异的患病率。
方法：我们在疑似单基因狼疮患者中完成了配对末端全基因组测序（全基因组测序[WGS]或全外显子组测序），专注于36个单基因狼疮基因。我们优先考虑稀有（次要等位基因频率<1％）外显子，非同义词，和具有预测致病性的剪接变体被分类为有害变体(组合注释依赖性缺失[CADD]，PolyPhen2，以及从耐受性[SIFT]评分中排序不耐受性)。通过考虑报告的接合性，额外的过滤仅限于预测的破坏性变体。在那些WGS（n=69），我们检查了大小>1kb的拷贝数变体(CNVs)。我们使用常见的SLE风险单核苷酸多态性创建了加性非HLA和HLASLE遗传风险评分（GRSs）。我们用多变量逻辑模型测试了SLEGRS与罕见变异数量之间的关系，适应性，祖先，和诊断年龄。
结果：该队列包括71名患者，80%女性,诊断时的平均年龄为8.9（SD3.2）岁。我们确定了9例（13％）患者的预测破坏性变异，这些患者在诊断时与没有预测破坏性变异的患者相比明显年轻（6.8[SD2.1]年vs9.2[SD3.2]年，P=0.01）。我们没有鉴定出破坏性的CNVs。在多变量分析中，非HLA或HLASLEGRS与携带≥1个罕见变异的几率之间没有显着关联。
结论：在接受全基因组测序的疑似单基因狼疮患者队列中，13%携带罕见的单基因狼疮预测破坏性变异。需要更多的研究来验证我们的发现。
方法：我们在疑似单基因狼疮患者中完成了配对末端全基因组测序（全基因组测序[WGS]或全外显子组测序），专注于36个单基因狼疮基因。我们优先考虑稀有（次要等位基因频率<1％）外显子，非同义词，和具有预测致病性的剪接变体被分类为有害变体(组合注释依赖性缺失[CADD]，PolyPhen2，以及从耐受性[SIFT]评分中排序不耐受性)。通过考虑报告的接合性，额外的过滤仅限于预测的破坏性变体。在那些WGS（n=69），我们检查了大小>1kb的拷贝数变体(CNVs)。我们使用常见的SLE风险单核苷酸多态性创建了加性非HLA和HLASLE遗传风险评分（GRSs）。我们用多变量逻辑模型测试了SLEGRS与罕见变异数量之间的关系，适应性，祖先，和诊断年龄。
结果：该队列包括71名患者，80%女性,诊断时的平均年龄为8.9（SD3.2）岁。我们确定了9例（13％）患者的预测破坏性变异，这些患者在诊断时与没有预测破坏性变异的患者相比明显年轻（6.8[SD2.1]年vs9.2[SD3.2]年，P=0.01）。我们没有鉴定出破坏性的CNVs。在多变量分析中，非HLA或HLASLEGRS与携带≥1个罕见变异的几率之间没有显着关联。
结论：在接受全基因组测序的疑似单基因狼疮患者队列中，13%携带罕见的单基因狼疮预测破坏性变异。需要更多的研究来验证我们的发现。
