Primary Immunodeficiency via the IRAK4 Gene

Interleukin-1 receptor-associated kinase (IRAK) 4 deficiency is a rare primary immunodeficiency disorder that results from impaired Toll-like receptor- (TLR) and interleukin1 (IL-1) receptor-mediated immune response (Picard et al. 2010). Patients with IRAK4 deficiency present with severe, recurrent, invasive bacterial infections, particularly Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa (Ku et al. 2007; Picard et al. 2010; Paciolla et al. 2015; Takada et al. 2016). In young children, the infections often lead to fatal pneumococcal meningitis (Ku et al. 2007; Picard et al. 2010; Takada et al. 2016). However, the frequency and severity of infections appears to decrease with age. In the largest patient series reported to date, no deaths were reported in children over 8 years of age and no infections were reported in children over 14 years of age (Picard et al. 2010). Prophylactic treatments, including antibiotics, antipneumococcal vaccinations, and/or IgG infusion, were reported to be beneficial until the teenage years with no apparent benefit thereafter (Picard et al. 2010). Genetic testing is helpful in distinguishing IRAK4 deficiency from chronic granulomatous disease, Hyper IgE syndromes, and other primary immunodeficiencies.

IRAK4 deficiency is inherited in an autosomal recessive fashion and is caused by homozygous or compound heterozygous pathogenic variants in the IRAK4 gene (Ku et al. 2007; Picard et al. 2010; Takada et al. 2016). The majority of pathogenic variants to date are truncating with nonsense, splice site, small insertions/deletions, and gross deletions being reported throughout the IRAK4 gene. Missense changes have also been reported in a few cases (Human Gene Mutation Database). No genotype-phenotype correlations have been reported to date (Ku et al. 2007; Picard et al. 2010; Takada et al. 2016). The IRAK4 gene encodes is a receptor kinase involved in mediating innate immune responses through TLR and IL-1 receptor pathways (Picard et al. 2010).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported (Ku et al. 2007; Picard et al. 2010; Takada et al. 2016). Analytical sensitivity should be high because the great majority of pathogenic variants reported to date are detectable by this method.

Only a few patients with IRAK4 deletions have been reported (Ku et al. 2007). However, these appear to be a rare cause of IRAK4 deficiency.

This test provides full coverage of all coding exons of the IRAK4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

This test also provides coverage of the c.1188+520A>G variant region.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).