Immunodeficiency 82 with systemic inflammation

Summary

Immunodeficiency 82 with systemic inflammation (MONDO:0030308) is a disease caused by SYK (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SYK (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 82 with systemic inflammation
Mondo ID	MONDO:0030308
OMIM	619381
Orphanet	695807
DOID	DOID:0061053
UMLS	C5543581
MedGen	1781752
Is cancer (heuristic)	no

Also known as: IMD82 · immunodeficiency 82 with systemic inflammation · immunodeficiency with systemic inflammation

Data availability: 12 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 82 with systemic inflammation

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 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, 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

12 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 1 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
989389	NM_003177.7(SYK):c.1649C>A (p.Ser550Tyr)	SYK	Pathogenic	criteria provided, single submitter
989387	NM_003177.7(SYK):c.1024C>A (p.Pro342Thr)	SYK	Likely pathogenic	criteria provided, single submitter
989386	NM_003177.7(SYK):c.1649C>T (p.Ser550Phe)	SYK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1683538	NM_003177.7(SYK):c.688G>A (p.Glu230Lys)	SYK	Uncertain significance	criteria provided, single submitter
1687481	NM_003177.7(SYK):c.1417G>C (p.Glu473Gln)	SYK	Uncertain significance	criteria provided, single submitter
3064741	NM_003177.7(SYK):c.1301G>A (p.Arg434Gln)	SYK	Uncertain significance	criteria provided, single submitter
3376354	NM_003177.7(SYK):c.163G>A (p.Val55Met)	SYK	Uncertain significance	criteria provided, single submitter
3892586	NM_003177.7(SYK):c.476C>T (p.Ala159Val)	SYK	Uncertain significance	criteria provided, single submitter
4076234	NM_003177.7(SYK):c.967del (p.Tyr323fs)	SYK	Uncertain significance	criteria provided, single submitter
4277837	NM_003177.7(SYK):c.1305G>A (p.Met435Ile)	SYK	Uncertain significance	criteria provided, single submitter
4846944	NM_003177.7(SYK):c.299T>C (p.Val100Ala)	SYK	Uncertain significance	criteria provided, single submitter
4846945	NM_003177.7(SYK):c.844G>C (p.Ala282Pro)	SYK	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
SYK	Strong	Autosomal dominant	immunodeficiency 82 with systemic inflammation	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYK	Orphanet:695807	Immunodeficiency-systemic inflammation-lymphoma predisposition syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYK	HGNC:11491	ENSG00000165025	P43405	Tyrosine-protein kinase SYK	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYK	Tyrosine-protein kinase SYK	Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYK	239	broad	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SYK	5,172

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SYK	P43405	93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FLT3 signaling through SRC family kinases	1	1631.4×	0.006	SYK
Interleukin-2 signaling	1	951.7×	0.006	SYK
FCGR activation	1	878.5×	0.006	SYK
Interleukin-2 family signaling	1	634.4×	0.006	SYK
Role of LAT2/NTAL/LAB on calcium mobilization	1	601.0×	0.006	SYK
Signaling by CSF3 (G-CSF)	1	571.0×	0.006	SYK
Regulation of signaling by CBL	1	496.5×	0.006	SYK
DAP12 interactions	1	475.8×	0.006	SYK
Role of phospholipids in phagocytosis	1	456.8×	0.006	SYK
Platelet Aggregation (Plug Formation)	1	439.2×	0.006	SYK
Inactivation of CSF3 (G-CSF) signaling	1	439.2×	0.006	SYK
Integrin signaling	1	423.0×	0.006	SYK
Dectin-2 family	1	423.0×	0.006	SYK
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.006	SYK
Leishmania parasite growth and survival	1	393.8×	0.006	SYK
DAP12 signaling	1	368.4×	0.006	SYK
FCERI mediated Ca+2 mobilization	1	356.9×	0.006	SYK
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	356.9×	0.006	SYK
FCERI mediated MAPK activation	1	346.1×	0.006	SYK
FLT3 Signaling	1	346.1×	0.006	SYK
Parasite infection	1	346.1×	0.006	SYK
Leishmania phagocytosis	1	346.1×	0.006	SYK
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.006	SYK
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	317.2×	0.006	SYK
GPVI-mediated activation cascade	1	308.6×	0.006	SYK
FCGR3A-mediated IL10 synthesis	1	292.8×	0.006	SYK
Fcgamma receptor (FCGR) dependent phagocytosis	1	278.5×	0.006	SYK
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.006	SYK
C-type lectin receptors (CLRs)	1	237.9×	0.007	SYK
FCGR3A-mediated phagocytosis	1	187.2×	0.008	SYK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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 interleukin-3 production	1	16852.0×	0.002	SYK
regulation of superoxide anion generation	1	16852.0×	0.002	SYK
regulation of arachidonate secretion	1	16852.0×	0.002	SYK
regulation of neutrophil degranulation	1	8426.0×	0.002	SYK
cellular response to lectin	1	8426.0×	0.002	SYK
leukocyte activation involved in immune response	1	5617.3×	0.002	SYK
serotonin secretion by platelet	1	5617.3×	0.002	SYK
beta selection	1	5617.3×	0.002	SYK
cellular response to molecule of fungal origin	1	4213.0×	0.002	SYK
positive regulation of mast cell cytokine production	1	3370.4×	0.002	SYK
regulation of platelet activation	1	2808.7×	0.002	SYK
positive regulation of alpha-beta T cell proliferation	1	2808.7×	0.002	SYK
interleukin-3-mediated signaling pathway	1	2407.4×	0.002	SYK
regulation of platelet aggregation	1	2407.4×	0.002	SYK
gamma-delta T cell differentiation	1	2106.5×	0.002	SYK
lymph vessel development	1	1872.4×	0.002	SYK
neutrophil activation involved in immune response	1	1872.4×	0.002	SYK
positive regulation of gamma-delta T cell differentiation	1	1872.4×	0.002	SYK
cell activation	1	1685.2×	0.002	SYK
positive regulation of alpha-beta T cell differentiation	1	1685.2×	0.002	SYK
regulation of phagocytosis	1	1685.2×	0.002	SYK
positive regulation of mast cell degranulation	1	1532.0×	0.002	SYK
obsolete regulation of DNA-binding transcription factor activity	1	1532.0×	0.002	SYK
cell surface pattern recognition receptor signaling pathway	1	1404.3×	0.002	SYK
leukotriene biosynthetic process	1	1296.3×	0.002	SYK
collagen-activated tyrosine kinase receptor signaling pathway	1	1296.3×	0.002	SYK
positive regulation of monocyte chemotactic protein-1 production	1	1203.7×	0.002	SYK
macrophage activation involved in immune response	1	1123.5×	0.002	SYK
positive regulation of B cell differentiation	1	1123.5×	0.002	SYK
positive regulation of cell adhesion mediated by integrin	1	1053.2×	0.002	SYK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SYK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SYK	54	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	SYK
NERATINIB	4	SYK
INFIGRATINIB PHOSPHATE	4	SYK
INFIGRATINIB	4	SYK
ENTRECTINIB	4	SYK
FOSTAMATINIB	4	SYK
CERITINIB	4	SYK
BOSUTINIB	4	SYK
GILTERITINIB	4	SYK
FOSTAMATINIB DISODIUM	4	SYK
PAZOPANIB	4	SYK
DASATINIB	4	SYK
ERLOTINIB	4	SYK
CRIZOTINIB	4	SYK
MIDOSTAURIN	4	SYK
IMATINIB	4	SYK
ENTOSPLETINIB	3	SYK
CEDIRANIB	3	SYK
QUERCETIN	3	SYK
LESTAURTINIB	3	SYK
FORETINIB	2	SYK
LUTEOLIN	2	SYK
REBASTINIB	2	SYK
APITOLISIB	2	SYK
CENISERTIB	2	SYK
ADAVOSERTIB	2	SYK
ILORASERTIB	2	SYK
R-343	2	SYK
FISETIN	2	SYK
TOP-1288	2	SYK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SYK	873	Binding:863, Functional:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SYK	2.7.10.2, 2.7.12.1	non-specific protein-tyrosine kinase, dual-specificity kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SYK	873

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
FEDRATINIB	4	SYK
NERATINIB	4	SYK
INFIGRATINIB PHOSPHATE	4	SYK
INFIGRATINIB	4	SYK
ENTRECTINIB	4	SYK
FOSTAMATINIB	4	SYK
CERITINIB	4	SYK
BOSUTINIB	4	SYK
GILTERITINIB	4	SYK
FOSTAMATINIB DISODIUM	4	SYK
PAZOPANIB	4	SYK
DASATINIB	4	SYK
ERLOTINIB	4	SYK
CRIZOTINIB	4	SYK
MIDOSTAURIN	4	SYK
IMATINIB	4	SYK
ENTOSPLETINIB	3	SYK
CEDIRANIB	3	SYK
QUERCETIN	3	SYK
LESTAURTINIB	3	SYK
FORETINIB	2	SYK
LUTEOLIN	2	SYK
REBASTINIB	2	SYK
APITOLISIB	2	SYK
CENISERTIB	2	SYK
ADAVOSERTIB	2	SYK
ILORASERTIB	2	SYK
R-343	2	SYK
FISETIN	2	SYK
TOP-1288	2	SYK

Druggability pyramid

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

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

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.