Abstract
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.
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Data and Materials Availability
The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code Availability
Not applicable.
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Acknowledgments
The sequence analysis was supported by the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima University.
Funding
This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (16H05355 and 19H03620 to SO), Promotion of Joint International Research from the Japan Society for the Promotion of Science (18KK0228 to SO), and the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, AMED (Grant Numbers: JP16ek0109179, JP19ek0109209, and JP20ek0109480) to S.O.
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All authors contributed to the accrual of subjects and/or data. SO contributed to the conception and design of the study. YI, TA, AP, and JLC drafted the manuscript. YI, MT, RK, and YM performed cellular assay and gene expression experiment. MT, TD, RN, MS, SK, KA, KI, TM, KK, and MK performed the clinical work and collected data. OO and SO analyzed data obtained by gene panel sequencing. All authors have revised the manuscript for important intellectual content and approved the final version.
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The study was approved by the ethics committees and institutional review board of Hiroshima University. All experiments were carried out with adherence to the Declaration of Helsinki.
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Imanaka, Y., Taniguchi, M., Doi, T. et al. Inherited CARD9 Deficiency in a Child with Invasive Disease Due to Exophiala dermatitidis and Two Older but Asymptomatic Siblings. J Clin Immunol 41, 975–986 (2021). https://doi.org/10.1007/s10875-021-00988-7
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DOI: https://doi.org/10.1007/s10875-021-00988-7