Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: TBK1

Green List (high evidence)

Comment on mode of inheritance: As reviewed before, there is sufficient evidence available for the association of monoallelic TBK1 variants to this panel based on {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8} phenotype (MIM #617900).

There is sufficient evidence available now (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder (MIM # 620880).

Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.

Created: 16 Jun 2025, 11:42 a.m. | Last Modified: 16 Jun 2025, 11:42 a.m.

Panel Version: 8.17

PMID:34363755 reported the identification of three different homozygous loss-of-function variants in TBK1 gene in four patients from three unrelated families. All of them presented with chronic and systemic autoinflammation, but not severe viral infections. Supporting functional evidence is also available.

Biallelic variants in this gene have also been associated with relevant phenotypes in OMIM (MIM #620880).

Created: 16 Jun 2025, 11:37 a.m. | Last Modified: 16 Jun 2025, 11:37 a.m.

Panel Version: 8.14

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
{Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8}, OMIM:617900; Autoinflammation with arthritis and vasculitis, OMIM:620880

Publications

• 34363755

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

Comment on list classification: Rating this gene green as there are 3 unrelated cases with a likely pathogenic mutation in this gene.

Created: 5 Jun 2018, 4:45 p.m.

In OMIM this gene is associated with Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8. OMIM reports 3 independent cases in which variants in this gene are thought to cause this phenotype. Firstly, Herman et al. (2012)(PMID: 22851595) report of 2 unrelated patients from Poland and France with herpes simplex encephalitis , Herman et al. (2012) identified heterozygous missense mutations in the TBK1 gene (G159A and D50A). Both are loss of function mutations (loss of kinase activity (G159A) and protein instability (D50A)). In vitro functional expression assays showed that the G159A mutation had a dominant-negative effect, whereas the D50A mutation resulted in haploinsufficiency. Neither variant was found in dbSNP (build 135) or in 1050 control human DNA samples. OMIM also cite Mork et al. (2015) (PMID: 26513235), who report a Danish woman (P10) with adult-onset herpes simplex encephalitis with a heterozygous missense mutation in the TBK1 gene (I207V). The variant was confirmed by Sanger sequencing, was not found in the ExAC database. No data about this gene in Gene2Phenotype. Rating this gene green as there are 3 unrelated cases with a likely pathogenic mutation in this gene.

Created: 5 Jun 2018, 4:43 p.m.

Comment on phenotypes: Added {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8}

Created: 5 Jun 2018, 3:12 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 22851595
• 26513235

Green List (high evidence)

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TBK1 .PanelApp HGNC gene symbol check: TBK1 . IUIS Disease: TBK1 deficiency . IUIS Inheritance: AD .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: CNS resident cells and fibroblasts. IUIS Associated features: Herpes simplex virus 1 encephalitis. IUIS Major category: Defects in Intrinsic and Innate Immunity. IUIS Subcategory: Herpes Simplex Encephalitis (HSE)

Created: 2 Jul 2018, 10:35 a.m.

Comment on mode of inheritance: added MOI from external expert review

Created: 13 Jun 2018, 10:23 a.m.

Comment on publications: added to support upgrading of the gene to Green

Created: 13 Jun 2018, 10:22 a.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s)
GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 19 Apr 2018, 1:34 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: TBK1, PanelApp HGNC gene symbol check: TBK1, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Defects in innate immunity / Herpetic encephalitis / Herpetic encephalitis (HSE)

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: TBK1, GRID_Gene_Symbol: TBK1, GRID_Transcript_ENS_Community submitted: ENST00000331710, GRID_Transcript_RefSeq: NM_013254.3, GRID_Transcript_ENS_used_on_Production: ENST00000331710

Created: 17 Apr 2018, 12:12 p.m.