Novel Bi-allelic Splice Mutations in CARD9 Causing Adult-onset Candida Endophthalmitis

Abstract

Background

CARD9 deficiency (CANDF2; OMIM# 212050) is an autosomal-recessive monogenic inborn error of immunity conferring susceptibility to invasive fungal diseases, including the very distinct syndrome of spontaneous central nervous system candidiasis, in which opportunistic yeasts of the genus Candida infect the central nervous system (either brain parenchyma and/or meninges) in the absence of trauma, chemotherapy or underlying systemic disease.

Methods

We present a patient with spontaneous endophthalmitis of the right eye due to Candida albicans; further investigations revealed concomitant cerebral abscess. She had a history of left endophthalmitis due to the dematiaceous mold, Aureobasidium pullulans, fifteen years earlier.

Results

Targeted sequencing of the CARD9 gene revealed two novel variants (c.184G>A and c.288C>T). Analysis in silico predicted each variant altered splicing, which was confirmed by sequencing of cDNA from proband and carrier offsprings: c.184G>A results in a 4-base pair frameshift deletion with loss of allelic expression; c.288C>T results in an in-frame 36-bp pair deletion with detectable protein.

Conclusion

CARD9 deficiency can present with a phenotype of spontaneous candidal endophthalmitis. We report two novel mutations in CARD9, both affecting splicing, expanding the range of morbid variants causing CARD9 deficiency, emphasizing the importance of both genomic and cDNA sequencing for this condition.

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