Clinical and Genetic Characterization of Patients with Artemis Deficiency in Japan
Clinical and Genetic Characterization of Patients with Artemis Deficiency in Japan
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DOI：
10.1007/s10875-022-01405-3
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发表时间：
2022-11-16
影响因子：
9.1
通讯作者：
Kanegane, Hirokazu
中科院分区：
文献类型：
--
作者：
Inoue, Kento;Miyamoto, Satoshi;Kanegane, Hirokazu
目的：Artemis是V(D)J重组和DNA双链断裂修复所必需的核酸外切酶。编码Artemis的DCLRE1C致病性变异导致T-B-NK+严重联合免疫缺陷（SCID），患有Artemis缺陷型SCID （ART-SCID）的患者需要同种异体造血细胞移植（HCT）的最终治疗。在这里，我们描述了2003年至2022年在日本诊断的ART-SCID患者的临床和遗传特征。方法采用问卷调查的方式收集2003 - 2022年日本ART-SCID患者的临床资料。结果来自7个家庭的8例患者在6个月内被ART-SCID诊断为严重感染。2例患者有错义变异，5例患者有大的基因组缺失，1例患者是复合杂合的错义变异和大的基因组缺失。所有8名患者在诊断后4个月内接受了同种异体HCT治疗，7名患者接受了含有烷基化剂的调理方案，1名患者因感染不受控制而未进行调理。2例表现不佳（PS）患者分别在hct后410天和32天死于并发症。6例存活患者中位随访时间为8.3（0.5-17.9）年，其中3例出现生长迟缓。PS 0-2级患者的总生存率高于PS 3-4级患者。结论大缺失是日本ART-SCID最常见的遗传原因。为了改善HCT结果，迫切需要通过新生儿筛查对SCID进行早期诊断。
Purpose Artemis is an exonuclease essential for V(D)J recombination and repair of DNA double-stranded breaks. Pathogenic variants in DCLRE1C encoding Artemis cause T-B-NK+ severe combined immunodeficiency (SCID), and patients with Artemis-deficient SCID (ART-SCID) require definitive therapy with allogeneic hematopoietic cell transplantation (HCT). Here we describe the clinical and genetic characteristics of patients with ART-SCID who were diagnosed in Japan from 2003 to 2022.Methods Clinical data of ART-SCID patients who were diagnosed between 2003 and 2022 in Japan were collected from their physicians using a questionnaire.Results ART-SCID diagnosis was made in eight patients from seven families with severe infections within 6 months of life. Two patients had missense variants, five patients had large genomic deletions, and one patient was compound heterozygous for a missense variant and large genomic deletion. All eight underwent allogeneic HCT within 4 months after the diagnosis, 7 receiving a conditioning regimen containing alkylating agents, and one patient without conditioning due to uncontrolled infection. Two patients with poor performance status (PS) died of complications 410 days and 32 days post-HCT, respectively. Of the six surviving patients with a median follow-up time of 8.3 (0.5-17.9) years, three patients had growth retardation. The patients with PS of 0-2 showed a tendency for better overall survival than those with PS 3-4.Conclusion Large deletions were the most common genetic cause of ART-SCID in Japan. To improve HCT outcome, early diagnosis with newborn screening for SCID is urgently needed.