Primary immunodeficiency
Gene: TLR8
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.Created: 3 Feb 2022, 9:07 a.m. | Last Modified: 3 Feb 2022, 9:07 a.m.
Panel Version: 2.526
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
Immunodeficiency; bone marrow failure; Autoinflammatory syndrome MONDO:0019751
Publications
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.Created: 15 Jan 2021, 11:36 a.m. | Last Modified: 15 Jan 2021, 11:36 a.m.
Panel Version: 2.390
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: LiteratureCreated: 26 Dec 2020, 11:34 p.m.
Mode of inheritance
Other
Phenotypes
neutropenia; lymphoproliferation; hypogammaglobulinemia; bone marrow failure
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mode of inheritance for gene: TLR8 was changed from Other to Unknown
Tag mosaicism tag was added to gene: TLR8. Tag somatic tag was added to gene: TLR8.
Gene: tlr8 has been classified as Red List (Low Evidence).
Publications for gene: TLR8 were set to 10.1182/blood.2020009620
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