目的:我们的目的是研究系统性红斑狼疮(SLE)早发性患者单基因病因的存在。
方法:本研究纳入了15例早期发病(≤6年)的儿童SLE患者。所有患者均符合系统性狼疮国际合作诊所(SLICC)标准。基因组DNA用于全外显子组测序(WES)。通过Sanger测序确认病原变异。
结果:纳入研究的15例早发性SLE患者的中位诊断年龄为4(2-6)岁(F/M=12/3)。在这些患者中有5例(33.3%)检测到明显的基因突变。具有纯合DNASE1L3突变[c.320+4_320+7del和G188A(c.563G>C)变体]的患者1和2有皮肤受累和口腔溃疡。其中一名患者(患者1)患有关节炎和肾炎,另一名患者(2例)有无瘢痕性脱发和血小板减少症.它们目前临床上不活跃,但具有阳性血清学结果。具有纯合致病性ACP5突变[G109R(c.325G>A)变体]的患者3患有关节炎,肾炎,身材矮小,和骨骼发育不良。具有杂合子新IFIH1突变[L809F(c.2425C>T)变体]的患者4具有皮肤发现和白细胞减少症。具有新的C1S变体[纯合C147W(c.441C>G)变体]的患者5具有明显的皮肤发现,口腔溃疡,无瘢痕性脱发,全血细胞减少症,和低总溶血补体CH50水平。所有患者对治疗有反应,系统性红斑狼疮疾病活动指数(SLEDAI)评分较低,关于治疗。
结论:应调查早发性SLE的遗传原因,为了更好的管理和遗传咨询。另一方面,多中心研究可能有助于进一步定义基因型-表型关联。
OBJECTIVE: We aimed to investigate the presence of monogenic causes of systemic lupus erythematosus (SLE) in our early-onset SLE patients.
METHODS: Fifteen pediatric SLE cases who had early disease onset (≤6 years) were enrolled in this study. All patients fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria. Genomic DNA was used for whole exome sequencing (WES). Pathogenic variants were confirmed by Sanger sequencing.
RESULTS: The median age at diagnosis of 15 early-onset SLE patients included in the study was 4 (2-6) years (F/M = 12/3). Significant gene mutations were detected in five of these patients (33.3%). Patients 1 and 2 with homozygous DNASE1L3 mutations [c.320+4_320+7del and G188 A (c.563 G>C) variants] had skin involvement and oral ulcers. One of them (patient 1) had arthritis and nephritis, and another (patient 2) had nonscarring alopecia and thrombocytopenia. They are currently clinically inactive but have positive serological findings. Patient 3 with homozygous pathogenic ACP5 mutation [G109 R (c.325 G>A) variant] had arthritis, nephritis, short stature, and skeletal dysplasia. Patient 4 with a heterozygote novel IFIH1 mutation [L809 F (c.2425 C>T) variant] had skin findings and leukopenia. Patient 5 with novel C1S variant [homozygous C147 W (c.441 C>G) variant] had marked skin findings, oral ulcers, nonscarring alopecia, pancytopenia, and low total hemolytic complement CH50 level. All patients have responded to the treatments and have low Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, on therapy.
CONCLUSIONS: Genetic causes should be investigated in early-onset SLE, for better management and genetic counseling. On the other hand, multicenter studies may help to further define genotype-phenotype associations.