Two novel compound heterozygous loss-of-function mutations cause fetal IRAK-4 deficiency presenting with Pseudomonas Aeruginosa sepsis

IF 4.5 3区 医学 Q2 IMMUNOLOGY
Fang Zhang , Zhiwei Wang , Shuai Men, Jinglu Zhang, Leilei Wang
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Abstract

Purpose

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.

两种新型复合杂合功能缺失突变导致胎儿IRAK-4缺乏症,并伴有绿脓杆菌败血症。
目的:报告一例五个月大的中国婴儿因白细胞介素-1受体相关激酶-4(IRAK-4)缺乏症而死亡的病例:方法:通过三重全外显子组测序和桑格测序确认了IRAK-4缺乏症的遗传学病因。方法:通过三全外显子组测序和桑格测序确认了 IRAK-4 缺乏症的遗传学病因,并使用体外微型基因剪接试验对其功能性后果进行了研究:结果:基因组DNA的三重全外显子测序发现了两个新的复合杂合突变,即IRAK-4 (NM_016123.3):c.942-1G > A和c.644_651+ 6delTTGCAGCAGTAAGT。据预测,这些突变会导致框架转换,并产生三个没有酶活性的截短蛋白:我们的研究结果扩大了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性支持。此外,本病例还强调了在处理以往健康儿童异常严重的感染时考虑潜在的免疫遗传缺陷的重要性,并强调了及时使用广谱抗微生物药物治疗的必要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Clinical immunology
Clinical immunology 医学-免疫学
CiteScore
12.30
自引率
1.20%
发文量
212
审稿时长
34 days
期刊介绍: Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.
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