Autoinflammatory Disorders

Gene: IRAK2

Red List (low evidence)

IRAK2 (interleukin 1 receptor associated kinase 2)
EnsemblGeneIds (GRCh38): ENSG00000134070
EnsemblGeneIds (GRCh37): ENSG00000134070
OMIM: 603304, Gene2Phenotype
IRAK2 is in 3 panels

2 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Red List (low evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Immune dysregulation, MONDO:0957790, IRAK2-related

Chirag Patel (Genetic Health Queensland)

Red List (low evidence)

PMID: 39299377
2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported. Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens). Paper does not comment on reasons for disease in biallelic and mono-allelic form.


Preprint paper:
2 individuals with immune dysregulation (1 x systemic lupus erythematosus and 1 x autoinflammatory disease) with same homozgyous exon 2 deletion in IRAK2 gene found on WES testing and confirmed with Sanger sequencing. Unaffected family members in trio were heterozygous for variant. Exon 2 encodes a proportion of the death domain, a critical protein domain for Myddosome assembly.

The patients exhibited aberrantly upregulated type I interferon (IFN) response following LPS stimulation, which was further confirmed in bone marrow-derived macrophages (BMDMs) in mice. RNA sequencing analysis indicated that PBMCs from the two patients consistently exhibited defects in activating NFkb signaling in response to LPS or R848 stimulation, as well as impaired activation of the MAPK signaling pathway. RNA sequencing demonstrated that BMDMs from Irak2 ∆ex2/∆ex2 mice exhibited defects in NFkb and MAPK signaling pathways, similar to patients’ PBMCs.
Sources: Literature
Created: 7 Nov 2024, 4:48 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Immune dysregulation, no OMIM #

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Immune dysregulation, MONDO:0957790, IRAK2-related
OMIM
603304
Clinvar variants
Variants in IRAK2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

8 Nov 2024, Gel status: 1

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: irak2 has been classified as Red List (Low Evidence).

8 Nov 2024, Gel status: 1

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: IRAK2 were changed from Immune dysregulation, no OMIM # to Immune dysregulation, MONDO:0957790, IRAK2-related

7 Nov 2024, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Chirag Patel (Genetic Health Queensland)

gene: IRAK2 was added gene: IRAK2 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature Mode of inheritance for gene: IRAK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: IRAK2 were set to PMID: 39299377 Phenotypes for gene: IRAK2 were set to Immune dysregulation, no OMIM # Review for gene: IRAK2 was set to RED