First Case of Patient With Two Homozygous Mutations in MYD88 and CARD9 Genes Presenting With Pyogenic Bacterial Infections, Elevated IgE, and Persistent EBV Viremia

Abstract

We described for the first time a female patient with the simultaneous presence of two homozygous mutations in MYD88 and CARD9 genes presenting with pyogenic bacterial infections, elevated IgE, and persistent EBV viremia. In addition to defective TLR/IL1R-signaling, we described novel functional alterations into the myeloid compartment. In particular, we demonstrated a defective production of reactive oxygen species exclusively in monocytes upon E. coli stimulation, the inability of immature mono-derived DCs (iDCs) to differentiate into mature DCs (mDCs) and the incapacity of mono-derived macrophages (MDMs) to resolve BCG infection in vitro . Our data do not provide any evidence for digenic inheritance in our patient, but rather for the association of two monogenic disorders. This case illustrates the importance of using next generation sequencing (NGS) to determine the most accurate and early diagnosis in atypical clinical and immunological phenotypes, and with particular concern in consanguineous families. Indeed, besides the increased susceptibility to recurrent invasive pyogenic bacterial infections due to MYD88 deficiency, the identification of CARD9 mutations underline the risk of developing invasive fungal infections emphasizing the careful monitoring for the occurrence of fungal infection and the opportunity of long-term antifungal prophylaxis.

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

“…In the second Ion Torrent negative patient (PID82) presenting an atypical HyperIgE syndrome, Haloplex detected two rare homozygous mutations in MYD88 and CARD9 genes, which were not included in the Ion Torrent panels (1 and 2). The pathogenic role of each single gene mutation is still under investigation but this molecular information is important to optimize the clinical management of the patient including the evaluation of HSCT as definitive treatment (44). In summary, 4 SCID/CID patients out of a total of 16 T cell defects, were identified by Haloplex, demonstrating once more a higher percentage of diagnosis in this PID group (Table 2B).…”

Superficial mycoses, a matter of concern: Global and Indian scenario‐an updated analysis

“…212 Mutations in CARD 9 and STAT 1 (transcription factor signal transducer and activator of transcription) predispose individuals to mycotic infections. 213,214 Homozygous mutations of CARD 9 and CARD 9 deficiency (autosomal recessive) have been observed to be associated with mucocutaneous candidiasis 215 and deep dermatophytosis, respectively. 212 Similarly, chronic mucocutaneous candidiasis (CMC) and hyper-IgE Syndrome (HIES), responsible for the defective mechanisms of mucosal host defence, are the primary immunodeficiencies caused due to mutations in STAT 1 (autosomal dominant gain of function mutations) and STAT 3 (dominant and negative mutations), respectively.…”

“…It is located downstream from C‐type receptors of lectin (such as dectin 1, dectin 2, dectin 3 and Mincle) which is involved in recognising the disease‐causing fungi 212 . Mutations in CARD 9 and STAT 1 (transcription factor signal transducer and activator of transcription) predispose individuals to mycotic infections 213,214 . Homozygous mutations of CARD 9 and CARD 9 deficiency (autosomal recessive) have been observed to be associated with mucocutaneous candidiasis 215 and deep dermatophytosis, respectively 212 …”

All Patients With Common Variable Immunodeficiency Disorders (CVID) Should Be Routinely Offered Diagnostic Genetic Testing

“…Our study confirms genes such as TNFRSF13B/ TACI have disease modifying effects on the severity of CVID-like disorders and supports the separation these two groups of mutations. Such digenic patients can only be identified by NGS (16, 54) and are a strong argument for sequencing both groups of genes, either causing CVID-like disorders ( NFKB1, NFKB2 , etc.) or those modifying the severity of CVID, such as TNFRSF13B/ TACI (19, 55).…”