CARD9 – Phaeohyphomycosis

Inherited autosomal recessive loss-of-function variants in the caspase recruitment domain-containing protein 9 gene (CARD9) underlie a unique primary immunodeficiency predisposing to phaeohyphomycosis (Phaeohyphomycosis; CARD9). Phaeohyphomycosis comprises chronic cutaneous, subcutaneous, or systemic infections caused by dematiaceous fungi, often in otherwise healthy individuals.

Genetic evidence includes over 20 unrelated probands harboring biallelic CARD9 variants. Reported alleles span missense (e.g., c.1118G>C (p.Arg373Pro)), frameshift (c.820dup (p.Glu274ArgfsTer?)), and nonsense/splice mutations across multiple families with autosomal recessive inheritance (PMID:31414217; PMID:35628702). Most cases are sporadic, but consanguineous pedigrees reveal homozygous mutations segregating with disease. The c.1118G>C (p.Arg373Pro) variant recurs in distinct cohorts, suggesting a possible founder effect in certain populations.

Functional studies demonstrate that patient-derived peripheral blood mononuclear cells and neutrophils with homozygous CARD9 variants exhibit markedly impaired proinflammatory cytokine production (IL-17A, TNF-α) and defective NF-κB activation upon fungal stimulation. Card9⁻/⁻ mice recapitulate human susceptibility, showing heightened fungal burden and lethal phaeohyphomycosis with diminished Th17/Th22 responses (PMID:29080677).

No studies have refuted the association, although fungal species–specific phenotypes vary in severity and tissue tropism. Detailed immunological phenotyping underscores that CARD9 deficiency specifically disrupts CLR–CARD9 signaling, leading to failure of BCL10/MALT1 signalosome assembly and downstream cytokine induction.

Integration of genetic and experimental data yields a Strong gene–disease association: autosomal recessive inheritance, >20 probands with concordant functional defects, and animal model validation. Genetic evidence qualifies as Strong (24 probands, multiple variant classes) and functional evidence as Moderate (cellular and murine concordance).

Key Take-Home: Genetic testing for CARD9 variants is recommended in patients presenting with unexplained phaeohyphomycosis, informing diagnosis and guiding immunological monitoring.

References

• The Journal of investigative dermatology • 2018 • Impaired Specific Antifungal Immunity in CARD9-Deficient Patients with Phaeohyphomycosis PMID:29080677
• Journal of clinical immunology • 2019 • The Phytopathogenic Fungus Pallidocercospora crystallina-Caused Localized Subcutaneous Phaeohyphomycosis in a Patient with a Homozygous Missense CARD9 Mutation PMID:31414217
• Journal of fungi (Basel, Switzerland) • 2022 • Invasive Rhinosinusitis Caused by Alternaria infectoria in a Patient with Autosomal Recessive CARD9 Deficiency and a Review of the Literature PMID:35628702

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