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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：I型干扰素病是一组罕见的自身免疫性疾病，其特征是I型干扰素的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毁伤修复中起主要感化。TREX1突变与许多I型干扰素病相关。已经发表了关于托法替尼治疗I型干扰素病的有效性的研究。这项研究的目的是确定中国I型干扰素病家族的致病变异，并观察托法替尼的治疗效果。
方法：调查了一个中国家庭，其中有两个成员患有I型干扰素病。使用患者及其家庭成员的外周血DNA应用全外显子组测序和Sanger测序进行突变筛查。使用包括VarCards和PolyPhen-2的生物信息学软件工具分析测序结果。通过密切的临床随访和观察记录托法替尼治疗前后疾病的变化。
结果:在患者基因组中观察到TREX1的复合杂合变体。一个是病人父亲的错觉变体（NM_016381;c.C227T;p.Ala76Val），另一个是来自患者母亲的移码变体（NM_016381;c.458dupA;p.Gln153Glnfs*3）。先证者的一位有类似皮肤病变的哥哥也携带了这两种变体。先证者的这位兄弟患有脑瘫合并症，皮肤受累更严重。这些TREX1变体在先前的研究中没有报道,并且被预测为高致病性的。先证者给予托法替尼，导致明显改善。
结论：我们在TREX1基因中发现了两个新的复杂杂合变体，这可能是该家族成员中观察到的I型干扰素病的分子发病机理的基础。托法替尼可能是这种疾病的替代疗法。
方法：调查了一个中国家庭，其中有两个成员患有I型干扰素病。使用患者及其家庭成员的外周血DNA应用全外显子组测序和Sanger测序进行突变筛查。使用包括VarCards和PolyPhen-2的生物信息学软件工具分析测序结果。通过密切的临床随访和观察记录托法替尼治疗前后疾病的变化。
结果:在患者基因组中观察到TREX1的复合杂合变体。一个是病人父亲的错觉变体（NM_016381;c.C227T;p.Ala76Val），另一个是来自患者母亲的移码变体（NM_016381;c.458dupA;p.Gln153Glnfs*3）。先证者的一位有类似皮肤病变的哥哥也携带了这两种变体。先证者的这位兄弟患有脑瘫合并症，皮肤受累更严重。这些TREX1变体在先前的研究中没有报道,并且被预测为高致病性的。先证者给予托法替尼，导致明显改善。
结论：我们在TREX1基因中发现了两个新的复杂杂合变体，这可能是该家族成员中观察到的I型干扰素病的分子发病机理的基础。托法替尼可能是这种疾病的替代疗法。
