Abstract：
OBJECTIVE: To report a case of a five-month-old Chinese infant who died of interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency presenting with rapid and progressive Pseudomonas aeruginosa sepsis.
METHODS: The genetic etiology of IRAK-4 deficiency was confirmed through trio-whole exome sequencing and Sanger sequencing. Functional consequences were invested using an in vitro minigene splicing assay.
RESULTS: Trio-whole exome sequencing of genomic DNA identified two novel compound heterozygous mutations, IRAK-4 (NM_016123.3): c.942-1G > A and c.644_651+ 6delTTGCAGCAGTAAGT in the proband, which originated from his symptom-free parents. These mutations were predicted to cause frameshifts and generate three truncated proteins without enzyme activity.
CONCLUSIONS: Our findings expand the range of IRAK-4 mutations and provide functional support for the pathogenic effects of splice-site mutations. Additionally, this case highlights the importance of considering the underlying genetic defects of immunity when dealing with unusually overwhelming infections in previously healthy children and emphasizes the necessity for timely treatment with wide-spectrum antimicrobials.
METHODS: The genetic etiology of IRAK-4 deficiency was confirmed through trio-whole exome sequencing and Sanger sequencing. Functional consequences were invested using an in vitro minigene splicing assay.
RESULTS: Trio-whole exome sequencing of genomic DNA identified two novel compound heterozygous mutations, IRAK-4 (NM_016123.3): c.942-1G > A and c.644_651+ 6delTTGCAGCAGTAAGT in the proband, which originated from his symptom-free parents. These mutations were predicted to cause frameshifts and generate three truncated proteins without enzyme activity.
CONCLUSIONS: Our findings expand the range of IRAK-4 mutations and provide functional support for the pathogenic effects of splice-site mutations. Additionally, this case highlights the importance of considering the underlying genetic defects of immunity when dealing with unusually overwhelming infections in previously healthy children and emphasizes the necessity for timely treatment with wide-spectrum antimicrobials.
摘要：
目的：报道一例5个月大的中国婴儿因白细胞介素-1受体相关激酶-4（IRAK-4）缺乏而死亡，表现为快速进展的铜绿假单胞菌败血症。
方法：通过三全外显子组测序和Sanger测序证实了IRAK-4缺陷的遗传病因。使用体外小基因剪接测定来投资功能后果。
结果：基因组DNA的三全外显子组测序鉴定了两个新的复合杂合突变，IRAK-4（NM_016123.3）：c.942-1G>A和c.644_6516delTTGCAGCAGTAAGT，起源于他无症状的父母.预测这些突变会导致移码并产生三种没有酶活性的截短蛋白。
结论：我们的发现扩大了IRAK-4突变的范围，并为剪接位点突变的致病作用提供了功能支持。此外,该病例强调了在处理先前健康儿童的异常压倒性感染时考虑免疫的潜在遗传缺陷的重要性,并强调了及时使用广谱抗菌药物治疗的必要性.
方法：通过三全外显子组测序和Sanger测序证实了IRAK-4缺陷的遗传病因。使用体外小基因剪接测定来投资功能后果。
结果：基因组DNA的三全外显子组测序鉴定了两个新的复合杂合突变，IRAK-4（NM_016123.3）：c.942-1G>A和c.644_6516delTTGCAGCAGTAAGT，起源于他无症状的父母.预测这些突变会导致移码并产生三种没有酶活性的截短蛋白。
结论：我们的发现扩大了IRAK-4突变的范围，并为剪接位点突变的致病作用提供了功能支持。此外,该病例强调了在处理先前健康儿童的异常压倒性感染时考虑免疫的潜在遗传缺陷的重要性,并强调了及时使用广谱抗菌药物治疗的必要性.
