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Primary immunodeficiency or monogenic inflammatory bowel disease v3.4 TLR8 Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: TLR8.
Primary immunodeficiency or monogenic inflammatory bowel disease v3.4 TLR8 Achchuthan Shanmugasundram reviewed gene: TLR8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v3.3 TLR8 Achchuthan Shanmugasundram Source Expert Review Green was added to TLR8.
Source NHS GMS was added to TLR8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.566 TLR8 Arina Puzriakova Publications for gene: TLR8 were set to 33512449; 34981838
Primary immunodeficiency or monogenic inflammatory bowel disease v2.565 TLR8 Arina Puzriakova Classified gene: TLR8 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.565 TLR8 Arina Puzriakova Added comment: Comment on list classification: Overall at least 7 unrelated families have been reported which support an association of TLR8 with immune dysfunction and autoinflammation, of which two families harboured germline variants. Functional data, including in vitro and animal model studies, corroborate pathogenicity of TLR8 variants. Therefore this gene can now be promoted to Green at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.565 TLR8 Arina Puzriakova Gene: tlr8 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.564 TLR8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TLR8.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.564 TLR8 Arina Puzriakova Publications for gene: TLR8 were set to https://doi.org/10.1182/blood.2020009620
Primary immunodeficiency or monogenic inflammatory bowel disease v2.563 TLR8 Arina Puzriakova Mode of inheritance for gene: TLR8 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.562 TLR8 Arina Puzriakova Phenotypes for gene: TLR8 were changed from neutropenia; lymphoproliferation; hypogammaglobulinemia; bone marrow failure to Immunodeficiency 98 with autoinflammation, X-linked, OMIM:301078
Primary immunodeficiency or monogenic inflammatory bowel disease v2.526 TLR8 Zornitza Stark changed review comment from: PMID 34981838: Monozygotic male twins, hemizygous for the G572V (maternally inherited), who had severe autoimmune haemolytic anaemia (AIHA) worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis and CNS vasculitis. Functional showed variant causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling.; to: PMID 34981838: Monozygotic male twins, hemizygous for the G572V (maternally inherited), who had severe autoimmune haemolytic anaemia (AIHA) worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis and CNS vasculitis. Functional showed variant causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling.

Further evidence for germline variants causing disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.526 TLR8 Zornitza Stark reviewed gene: TLR8: Rating: GREEN; Mode of pathogenicity: None; Publications: 34981838; Phenotypes: Immunodeficiency, bone marrow failure, Autoinflammatory syndrome MONDO:0019751; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v2.391 TLR8 Arina Puzriakova Mode of inheritance for gene: TLR8 was changed from Other to Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.390 TLR8 Arina Puzriakova Tag mosaicism tag was added to gene: TLR8.
Tag somatic tag was added to gene: TLR8.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.390 TLR8 Arina Puzriakova Classified gene: TLR8 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.390 TLR8 Arina Puzriakova Added comment: Comment on list classification: 6 unrelated individuals with relevant phenotype, associated with variants in this gene (https://doi.org/10.1182/blood.2020009620). However, 5 cases had somatic mosaicism and this panel is not appropriate for somatic variant detection due to coverage. Therefore, rating Red but this may be reviewed if additional cases with germline variants emerge.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.390 TLR8 Arina Puzriakova Gene: tlr8 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.389 TLR8 Arina Puzriakova Publications for gene: TLR8 were set to 10.1182/blood.2020009620
Primary immunodeficiency or monogenic inflammatory bowel disease v2.387 TLR8 Boaz Palterer gene: TLR8 was added
gene: TLR8 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TLR8 was set to Other
Publications for gene: TLR8 were set to 10.1182/blood.2020009620
Phenotypes for gene: TLR8 were set to neutropenia; lymphoproliferation; hypogammaglobulinemia; bone marrow failure
Penetrance for gene: TLR8 were set to unknown
Mode of pathogenicity for gene: TLR8 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TLR8 was set to AMBER
Added comment: Aluri et al. (Blood 2020, 10.1182/blood.2020009620) identified six unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and bone marrow failure associated with three different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8).
The variants are functionally gain-of-function and all patients are males, it's unclear if heterozygous females are affected. Both germline and somatic variants have been identified, but somatic mutations appear to be prominent.
Sources: Literature