Beppu Shiro, Nishikawa Takuro, Tomomasa Dan, Hijikata Atsushi, Kasabata Hiroshi, Terazono Hideyuki, Ikawa Kazuro, Nakamura Tatsuro, Horikawa Shogo, Nagahama Jun, Nakamura Aki, Abematsu Takanari, Nakagawa Shunsuke, Oketani Kaoru, Kanegane Hirokazu, Okamoto Yasuhiro
Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Front Immunol. 2024 Nov 20;15:1478411. doi: 10.3389/fimmu.2024.1478411. eCollection 2024.
Newborn screening (NBS) for severe combined immunodeficiency (SCID) has improved the prognosis of SCID. In Japan, NBS testing (measurement of the T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC)) was launched in 2017 and has expanded nationwide in recent years. In this study, we report a Japanese patient with X-linked SCID with a novel variant identified through NBS. The patient underwent cord blood transplantation (CBT).
The patient had no siblings or family history of inborn errors of immunity. He was born at 38 weeks of gestation and weighed 3,072 g. His NBS results revealed TREC 0 copies/10 cells (normal value: >565 copies/10 cells), which was considered suggestive of SCID. The patient was referred to our hospital. Although his lymphocyte count was 1,402/μL, naïve T cells and CD56 natural killer (NK) cells were decreased to 0% and 0.05% of the total lymphocytes, respectively. Flow cytometric measurement testing revealed a decrease in γc protein expression in the B lymphocytes and NK lymphocytes. We identified a hemizygous novel missense variant (c.256A>C, p.Thr86Pro) of . Both and structural analyses revealed that this variant is likely pathogenic. At 3 months of age, he underwent CBT from a human leukocyte antigen-full-matched unrelated donor. The conditioning regimen included fludarabine (180 mg/m) and targeted busulfan (35 mg×h/L). The patient achieved high-level donor chimerism and immune reconstitution, including B-cell function, at 13 months.
Using NBS, the patient was diagnosed as having X-linked SCID with a novel missense variant of . Early diagnosis using NBS tests enables safe hematopoietic stem cell transplantation without complications such as infection. We also found that even SCID with novel variants can be accurately diagnosed using the NBS program. In Japan, the test uptake rate is approximately 80% due to the high number of self-funded screening tests, and it is hoped that the uptake rate will increase in the future.
严重联合免疫缺陷病（SCID）的新生儿筛查（NBS）改善了SCID的预后。在日本，NBS检测（T细胞受体切除环（TREC）和κ-缺失重组切除环（KREC）的测量）于2017年启动，近年来已在全国范围内推广。在本研究中，我们报告了一名通过NBS鉴定出新型变异的日本X连锁SCID患者。该患者接受了脐带血移植（CBT）。
该患者无免疫缺陷病的兄弟姐妹或家族史。他在妊娠38周时出生，体重3072克。他的NBS结果显示TREC为0拷贝/10个细胞（正常值：>565拷贝/10个细胞），这被认为提示SCID。该患者被转诊至我院。尽管他的淋巴细胞计数为1402/μL，但初始T细胞和CD56自然杀伤（NK）细胞分别降至总淋巴细胞的0%和0.05%。流式细胞术检测显示B淋巴细胞和NK淋巴细胞中γc蛋白表达降低。我们鉴定出一种半合子新型错义变异（c.256A>C，p.Thr86Pro）。 和结构分析均表明该变异可能具有致病性。在3个月大时，他接受了来自人类白细胞抗原完全匹配的无关供体的CBT。预处理方案包括氟达拉滨（180mg/m）和靶向白消安（35mg×h/L）。患者在13个月时实现了高水平的供体嵌合和免疫重建，包括B细胞功能。
通过NBS，该患者被诊断为具有新型错义变异的X连锁SCID。使用NBS检测进行早期诊断可实现安全的造血干细胞移植，而无感染等并发症。我们还发现，即使是具有新型变异的SCID也可通过NBS程序准确诊断。在日本，由于自费筛查检测数量众多，检测接受率约为80%，希望未来接受率会有所提高。
