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| Defects of intrinsic and innate immunity v0.135 | IRAK2 |
Chirag Patel changed review comment from: 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. Sources: Literature; to: 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. |
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| Defects of intrinsic and innate immunity v0.135 | IRAK2 |
Chirag Patel gene: IRAK2 was added gene: IRAK2 was added to Defects of innate immunity. 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 Review for gene: IRAK2 was set to RED Added comment: 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. Sources: Literature |
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| Defects of intrinsic and innate immunity v0.94 | IRAK4 | Zornitza Stark Marked gene: IRAK4 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Defects of intrinsic and innate immunity v0.94 | IRAK4 | Zornitza Stark Gene: irak4 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Defects of intrinsic and innate immunity v0.94 | IRAK4 | Zornitza Stark Phenotypes for gene: IRAK4 were changed from to Immunodeficiency 67, MIM# 607676 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Defects of intrinsic and innate immunity v0.93 | IRAK4 | Zornitza Stark Publications for gene: IRAK4 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Defects of intrinsic and innate immunity v0.92 | IRAK4 | Zornitza Stark Mode of inheritance for gene: IRAK4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Defects of intrinsic and innate immunity v0.91 | IRAK4 | Zornitza Stark reviewed gene: IRAK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26825884, 17878374, 17544092, 16950813; Phenotypes: Immunodeficiency 67, MIM# 607676; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Defects of intrinsic and innate immunity v0.0 | IRAK4 |
Zornitza Stark gene: IRAK4 was added gene: IRAK4 was added to Defects of innate immunity_MGHA_AGHA_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services,Melbourne Genomics Health Alliance Immunology Flagship Mode of inheritance for gene: IRAK4 was set to Unknown |
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