Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
Department of Medical Genetics and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
Pediatr Rheumatol Online J. 2021 Jan 6;19(1):1. doi: 10.1186/s12969-020-00490-1.
Type I interferonopathies are a group of rare autoimmune diseases characterised by excessive activation of type I interferon that leads to disturbances in immune function. Three prime repair exonuclease 1 (TREX1) is an important exonuclease and plays an important role in DNA damage repair. TREX1 mutations are associated with many type I interferonopathies. Studies have been published on the effectiveness of tofacitinib in the treatment of type I interferonopathies. The aim of this study is to identify the pathogenic variation in a Chinese family with type I interferonopathies and to observe the therapeutic effects of tofacitinib.
A Chinese family with two members with type I interferonopathies was investigated. Whole exome sequencing and Sanger sequencing were applied for mutation screening using peripheral blood DNA of the patient and her family members. Sequencing results were analysed using bioinformatics software tools including VarCards and PolyPhen-2. Close clinical follow-up and observation were used to record changes in the disease before and after treatment with tofacitinib.
Compound heterozygous variants of TREX1 were observed in the patient's genome. One was a missense variant (NM_016381; c.C227T; p.Ala76Val) from the patient's father, and the other was a frameshift variant (NM_016381; c.458dupA; p.Gln153Glnfs*3) from the patient's mother. One of the proband's elder brothers with similar skin lesions also carried these two variants. This brother of the proband had more serious cutaneous involvement with the comorbidity of cerebral palsy. These TREX1 variants have not been reported in previous studies and are predicted to be highly pathogenic. The proband was given tofacitinib that led to a marked improvement.
We identified two novel complex heterozygous variants in the TREX1 gene, which may underlie the molecular pathogenesis of the type I interferonopathies observed in members of this family. Tofacitinib could be an alternative treatment for this disease.
I 型干扰素病是一组罕见的自身免疫性疾病，其特征是 I 型干扰素过度激活，导致免疫功能紊乱。三引物修复外切酶 1（TREX1）是一种重要的外切酶，在 DNA 损伤修复中发挥重要作用。TREX1 突变与许多 I 型干扰素病有关。已经发表了关于托法替尼治疗 I 型干扰素病的疗效的研究。本研究旨在鉴定一个中国 I 型干扰素病家系的致病变异，并观察托法替尼的治疗效果。
对一个有两名 I 型干扰素病患者的中国家庭进行了研究。应用全外显子组测序和 Sanger 测序，对患者及其家庭成员的外周血 DNA 进行突变筛查。使用 VarCards 和 PolyPhen-2 等生物信息学软件工具对测序结果进行分析。通过密切的临床随访和观察，记录患者在接受托法替尼治疗前后疾病的变化。
在患者的基因组中观察到 TREX1 的复合杂合变异。一个是来自患者父亲的错义变异（NM_016381；c.C227T；p.Ala76Val），另一个是来自患者母亲的框移变异（NM_016381；c.458dupA；p.Gln153Glnfs*3）。患者的一位有类似皮肤损伤的哥哥也携带这两种变异。这位患者的哥哥皮肤受累更严重，合并脑瘫。这些 TREX1 变异以前没有报道过，预测为高度致病性。给予患者托法替尼治疗后，病情明显改善。
我们在 TREX1 基因中发现了两个新的复合杂合变异，这可能是该家系中观察到的 I 型干扰素病的分子发病机制。托法替尼可能是这种疾病的一种替代治疗方法。
