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Inherited CARD9 Deficiency in a Child with Invasive Disease Due to Exophiala dermatitidis and Two Older but Asymptomatic Siblings

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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.

Author information

Author notes

  1. Takaki Asano

    Present address: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA

  2. Masao Kobayashi

    Present address: Japan Red Cross, Chugoku-Shikoku Block Blood Center, Hiroshima, Japan

Authors and Affiliations

  1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Science, Hiroshima, Japan

    Yusuke Imanaka, Maki Taniguchi, Takehiko Doi, Miyuki Tsumura, Maiko Shimomura, Takaki Asano, Reiko Kagawa, Yoko Mizoguchi, Shuhei Karakawa, Masao Kobayashi & Satoshi Okada

  2. Division of Infectious Diseases Laboratory Medicine, Hiroshima University Hospital, Hiroshima, Japan

    Rie Nagaoka

  3. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA

    Jean-Laurent Casanova & Anne Puel

  4. Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan

    Koji Arihiro

  5. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Kohsuke Imai & Tomohiro Morio

  6. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, Paris, France

    Jean-Laurent Casanova & Anne Puel

  7. University of Paris, Paris, France

    Jean-Laurent Casanova & Anne Puel

  8. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  9. Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan

    Osamu Ohara

  10. Department of Medical Mycology Research Center, Chiba University, Chiba, Japan

    Katsuhiko Kamei

Authors
  1. Yusuke Imanaka
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  2. Maki Taniguchi
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  3. Takehiko Doi
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  4. Miyuki Tsumura
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  6. Maiko Shimomura
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  19. Satoshi Okada
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Contributions

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.

Corresponding author

Correspondence to Satoshi Okada.

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Ethics Approval

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.

Consent to Participate

Informed consent was obtained from the guardians of the pediatric patients or directly from participants.

Consent for Publication

Informed consent was obtained from the guardians of the pediatric patients for publication of this case report and accompanying images.

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The authors declare that there is no conflict of interest.

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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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