immunodeficiency 98 with autoinflammation, X-linked

Summary

immunodeficiency 98 with autoinflammation, X-linked (MONDO:0024777) is a disease caused by TLR8 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TLR8 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 98 with autoinflammation, X-linked
Mondo ID	MONDO:0024777
OMIM	301078
Orphanet	675628
DOID	DOID:0061068
UMLS	C5676883
MedGen	1805285
GARD	0027130
Is cancer (heuristic)	no

Also known as: IMD98 · immunodeficiency 98 with autoinflammation, X-linked · inflammation, neutropenia, bone marrow failure, and lymphoproliferation caused by TLR8 · X-linked immunodeficiency with autoinflammation

Data availability: 11 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 98 with autoinflammation, X-linked

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

11 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 3 pathogenic, 2 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172678	NM_138636.5(TLR8):c.1715G>A (p.Gly572Asp)	TLR8	Pathogenic	no assertion criteria provided
1172679	NM_138636.5(TLR8):c.1482C>A (p.Phe494Leu)	TLR8	Pathogenic	no assertion criteria provided
1339649	NM_138636.5(TLR8):c.1715G>T (p.Gly572Val)	TLR8	Pathogenic	criteria provided, single submitter
4277487	NM_138636.5(TLR8):c.396del (p.Glu133fs)	TLR8	Likely pathogenic	criteria provided, single submitter
4279980	NM_138636.5(TLR8):c.1481T>A (p.Phe494Tyr)	TLR8	Likely pathogenic	criteria provided, single submitter
1172677	NM_138636.5(TLR8):c.1295C>T (p.Pro432Leu)	TLR8	Uncertain significance	criteria provided, single submitter
3065821	NM_138636.5(TLR8):c.3029C>G (p.Ala1010Gly)	TLR8	Uncertain significance	criteria provided, single submitter
3341294	NM_138636.5(TLR8):c.328C>G (p.Gln110Glu)	TLR8	Uncertain significance	criteria provided, single submitter
3376338	NM_138636.5(TLR8):c.91T>C (p.Ser31Pro)	TLR8	Uncertain significance	criteria provided, multiple submitters, no conflicts
3457100	NM_138636.5(TLR8):c.286C>T (p.His96Tyr)	TLR8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1170509	NM_000639.3(FASLG):c.259T>C (p.Phe87Leu)	FASLG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TLR8	Strong	X-linked	immunodeficiency 98 with autoinflammation, X-linked	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TLR8	Orphanet:675628	TLR8-related inflammation-severe neutropenia-bone marrow failure-lymphoproliferation syndrome
FASLG	Orphanet:3261	Autoimmune lymphoproliferative syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TLR8	HGNC:15632	ENSG00000101916	Q9NR97	Toll-like receptor 8	gencc,clinvar
FASLG	HGNC:11936	ENSG00000117560	P48023	Tumor necrosis factor ligand superfamily member 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TLR8	Toll-like receptor 8	Endosomal receptor that plays a key role in innate and adaptive immunity.
FASLG	Tumor necrosis factor ligand superfamily member 6	Cytokine that binds to TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TLR8	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt
FASLG	Other/Unknown	no		TNF_dom, TNF, Tumour_necrosis_fac-like_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
blood	1
granulocyte	1
lymph node	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TLR8	174	broad	marker	monocyte, mononuclear cell, leukocyte
FASLG	118	tissue_specific	marker	granulocyte, blood, lymph node

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FASLG	4,373
TLR8	3,532

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TLR8	Q9NR97	39
FASLG	P48023	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FasL/ CD95L signaling	1	1142.0×	0.006	FASLG
Regulation by c-FLIP	1	519.1×	0.006	FASLG
CASP8 activity is inhibited	1	519.1×	0.006	FASLG
Dimerization of procaspase-8	1	519.1×	0.006	FASLG
Trafficking and processing of endosomal TLR	1	407.9×	0.006	TLR8
Caspase activation via Death Receptors in the presence of ligand	1	380.7×	0.006	FASLG
FOXO-mediated transcription of cell death genes	1	356.9×	0.006	FASLG
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	259.6×	0.008	FASLG
RIPK1-mediated regulated necrosis	1	228.4×	0.008	FASLG
TNFs bind their physiological receptors	1	196.9×	0.008	FASLG
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	92.1×	0.015	TLR8
TNFR2 non-canonical NF-kB pathway	1	90.6×	0.015	FASLG
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.024	FASLG
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.025	TLR8
Cytokine Signaling in Immune system	1	20.4×	0.052	FASLG
Immune System	1	6.5×	0.148	FASLG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of phosphatidylserine exposure on apoptotic cell surface	1	8426.0×	0.003	FASLG
inflammatory cell apoptotic process	1	4213.0×	0.003	FASLG
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1	4213.0×	0.003	FASLG
toll-like receptor 8 signaling pathway	1	2808.7×	0.003	TLR8
retinal cell programmed cell death	1	2808.7×	0.003	FASLG
positive regulation of canonical NF-kappaB signal transduction	2	72.6×	0.003	TLR8, FASLG
necroptotic signaling pathway	1	1053.2×	0.006	FASLG
intracellular chloride ion homeostasis	1	842.6×	0.006	FASLG
response to growth factor	1	702.2×	0.006	FASLG
T cell apoptotic process	1	648.1×	0.006	FASLG
endosomal lumen acidification	1	601.9×	0.006	FASLG
necroptotic process	1	526.6×	0.007	FASLG
positive regulation of endothelial cell apoptotic process	1	366.4×	0.009	FASLG
immunoglobulin mediated immune response	1	351.1×	0.009	TLR8
positive regulation of interferon-alpha production	1	324.1×	0.009	TLR8
toll-like receptor signaling pathway	1	300.9×	0.009	TLR8
positive regulation of innate immune response	1	263.3×	0.010	TLR8
positive regulation of epidermal growth factor receptor signaling pathway	1	247.8×	0.010	FASLG
positive regulation of extrinsic apoptotic signaling pathway	1	227.7×	0.010	FASLG
extrinsic apoptotic signaling pathway via death domain receptors	1	200.6×	0.010	FASLG
positive regulation of interferon-beta production	1	195.9×	0.010	TLR8
canonical NF-kappaB signal transduction	1	183.2×	0.011	TLR8
extrinsic apoptotic signaling pathway	1	153.2×	0.012	FASLG
positive regulation of neuron apoptotic process	1	135.9×	0.013	FASLG
positive regulation of interleukin-1 beta production	1	129.6×	0.013	TLR8
positive regulation of interleukin-8 production	1	122.1×	0.014	TLR8
positive regulation of type II interferon production	1	112.3×	0.014	TLR8
apoptotic signaling pathway	1	112.3×	0.014	FASLG
cellular response to mechanical stimulus	1	108.0×	0.014	TLR8
cellular response to type II interferon	1	104.0×	0.014	FASLG

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TLR8	8	2
FASLG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VESATOLIMOD	2	TLR8
MOTOLIMOD	2	TLR8
RESIQUIMOD	2	TLR8
GSK-2245035	2	TLR8
SELGANTOLIMOD	2	TLR8
AFIMETORAN	2	TLR8
ENPATORAN	2	TLR8
MHV-370	2	TLR8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TLR8	395	Binding:378, Functional:16, ADMET:1
FASLG	2	Binding:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TLR8	395

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

8 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
VESATOLIMOD	2	TLR8
MOTOLIMOD	2	TLR8
RESIQUIMOD	2	TLR8
GSK-2245035	2	TLR8
SELGANTOLIMOD	2	TLR8
AFIMETORAN	2	TLR8
ENPATORAN	2	TLR8
MHV-370	2	TLR8

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	TLR8
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FASLG

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FASLG	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.