Inherited CARD9 Deficiency in a Child with Invasive Disease Due to Exophiala dermatitidis and Two Older but Asymptomatic Siblings
Inherited CARD9 Deficiency in a Child with Invasive Disease Due to Exophiala dermatitidis and Two Older but Asymptomatic Siblings
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DOI：
10.1007/s10875-021-00988-7
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发表时间：
2021-02-08
影响因子：
9.1
通讯作者：
Okada, Satoshi
中科院分区：
文献类型：
--
作者：
Imanaka, Yusuke;Taniguchi, Maki;Okada, Satoshi
目的 常染色体隐性遗传 CARD9 缺陷使患者易患侵袭性真菌病。念珠菌和毛癣菌是这些患者真菌病的主要原因。其他 CARD9 缺陷患者表现出由其他真菌（例如 Exophiala spp）引起的侵袭性疾病。令人惊讶的是，与真菌疾病相关的 CARD9 缺陷的临床外显率直到成年才完全，但年龄仍不清楚。此外，尚未报道经基因证实但无症状的 CARD9 缺陷个体的免疫学特征。方法 通过基因组测序鉴定 CARD9 突变，并通过定量 PCR、免疫印迹、荧光素酶报告基因和流式细胞珠阵列分析表征细胞表型。结果 基因组测序在一名 4 岁患者中发现了复合杂合 CARD9 变异，c.1118G>C (p.R373P) 和 c.586A>G (p.K196E)，该患者因外管皮炎而患有多发性脑损伤和全身淋巴结肿大。 p.R373P 是一种已知的致病变异，而 p.K196E 是一种私人变异。尽管该患者的兄弟姐妹（一名10岁的兄弟和一名8岁的姐妹）也是复合杂合子，但迄今为止他们一直没有症状。在患者的CD14(+)单核细胞中发现正常的CARD9 mRNA和蛋白表达。然而，这些细胞在响应真菌刺激时表现出明显受损的促炎细胞因子产生。来自两个无症状兄弟姐妹的单核细胞表现出相同的细胞表型。结论 对于既往健康的侵袭性外口皮炎患者，应考虑 CARD9 缺陷。所有年龄段的无症状亲属均应接受 CARD9 缺陷检测。检测无症状个体的细胞缺陷对于诊断 CARD9 缺陷很有用。
Purpose Autosomal recessive CARD9 deficiency predisposes patients to invasive fungal disease. Candida and Trichophyton species are major causes of fungal disease in these patients. Other CARD9-deficient patients display invasive diseases caused by other fungi, such as Exophiala spp. The clinical penetrance of CARD9 deficiency regarding fungal disease is surprisingly not complete until adulthood, though the age remains unclear. Moreover, the immunological features of genetically confirmed yet asymptomatic individuals with CARD9 deficiency have not been reported. Methods Identification of CARD9 mutations by gene panel sequencing and characterization of the cellular phenotype by quantitative PCR, immunoblot, luciferase reporter, and cytometric bead array assays were performed. Results Gene panel sequencing identified compound heterozygous CARD9 variants, c.1118G>C (p.R373P) and c.586A>G (p.K196E), in a 4-year-old patient with multiple cerebral lesions and systemic lymphadenopathy due to Exophiala dermatitidis. The p.R373P is a known disease-causing variant, whereas the p.K196E is a private variant. Although the patient's siblings, a 10-year-old brother and an 8-year-old sister, were also compound heterozygous, they have been asymptomatic to date. Normal CARD9 mRNA and protein expression were found in the patient's CD14(+) monocytes. However, these cells exhibited markedly impaired pro-inflammatory cytokine production in response to fungal stimulation. Monocytes from both asymptomatic siblings displayed the same cellular phenotype. Conclusions CARD9 deficiency should be considered in previously healthy patients with invasive Exophiala dermatitidis disease. Asymptomatic relatives of all ages should be tested for CARD9 deficiency. Detecting cellular defects in asymptomatic individuals is useful for diagnosing CARD9 deficiency.