IRAK4 – Immunodeficiency 67

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that mediates Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling, critical for innate immune responses. Biallelic loss-of-function variants in IRAK4 cause autosomal recessive immunodeficiency 67, characterized by recurrent, invasive pyogenic bacterial infections and often attenuated systemic inflammatory markers despite severe disease ([PMID:24717963]).

Genetic analyses across multiple cohorts have identified at least 12 unrelated probands with IRAK4 deficiency, harboring seven distinct pathogenic variants, including frameshift, splice-site, and duplication mutations consistent with loss of protein function ([PMID:26698383]; [PMID:24717963]). Segregation of homozygous or compound heterozygous variants in affected siblings and extended kindreds confirms autosomal recessive inheritance and high penetrance ([PMID:16647422]).

Affected individuals commonly present in infancy with severe bacterial infections such as pneumococcal meningitis, liver abscess complicated by pleural empyema, and Pseudomonas sepsis. Segregation analysis in one consanguineous kindred showed three fourth-degree relatives with biallelic IRAK4 variants, and two siblings in another family were compound heterozygotes, yielding at least five additional affected relatives with confirmed variant segregation ([PMID:16647422]; [PMID:26698383]).

The variant spectrum includes c.255_260dup (p.Asp86_Leu87dup), c.1146del (p.Gly383fs), c.1049delG (p.Gly350GlufsTer15), c.877C>T (p.Gln293Ter), c.274del (p.Glu92AsnfsTer27), and splice-site mutations, all predicted or shown to abolish IRAK4 protein expression. The recurrent c.255_260dup (p.Asp86_Leu87dup) duplication has been observed in multiple kindreds, suggesting a founder or hotspot effect ([PMID:26698383]).

Functional studies demonstrate absent or markedly reduced IRAK4 protein in patient cells, failure of IRAK1 phosphorylation after TLR stimulation, and impaired neutrophil activation—oxidative burst, CD11b upregulation, and cytokine production—upon TLR1/2, TLR2/6, TLR4, and TLR7/8 agonist challenge. Notably, TLR9-mediated neutrophil responses remain intact via a PI3K-dependent bypass, delineating pathway specificity ([PMID:17878374]; [PMID:32532880]).

Together, the concordant genetic segregation, variant pathogenicity, and functional impairment of innate immune signaling support a Strong ClinGen classification for the IRAK4–immunodeficiency 67 association. Early genetic screening and functional assays facilitate definitive diagnosis, guide antimicrobial prophylaxis, and inform consideration of adjunctive therapies (e.g., immunoglobulin replacement). Key take-home: IRAK4 deficiency is an autosomal recessive disorder presenting with life-threatening pyogenic infections and specific TLR signaling defects, warranting prompt molecular and immunological evaluation in infancy.

References

• The Pediatric infectious disease journal • 2014 • Liver abscess complicated by diaphragm perforation and pleural empyema leads to the discovery of interleukin-1 receptor-associated kinase 4 deficiency PMID:24717963
• Clinical immunology (Orlando, Fla.) • 2016 • IRAK-4 deficiency as a cause for familial fatal invasive infection by Streptococcus pneumoniae PMID:26698383
• Cold Spring Harbor molecular case studies • 2020 • Clinical IRAK4 deficiency caused by homozygosity for the novel IRAK4 (c.1049delG, p.Gly350Glufs*15) variant PMID:32532880
• Journal of immunology (Baltimore, Md. : 1950) • 2007 • TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway PMID:17878374
• The Journal of pediatrics • 2006 • Autosomal recessive interleukin-1 receptor-associated kinase 4 deficiency in fourth-degree relatives PMID:16647422

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