pyogenic bacterial infections due to MyD88 deficiency

Summary

pyogenic bacterial infections due to MyD88 deficiency (MONDO:0012839) is a disease caused by MYD88 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: MYD88 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 161

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pyogenic bacterial infections due to MyD88 deficiency
Mondo ID	MONDO:0012839
MeSH	C567379
OMIM	612260
Orphanet	183713
ICD-11	444523526
UMLS	C2677092
MedGen	383023
GARD	0012638
Is cancer (heuristic)	no

Also known as: immunodeficiency 68 · MyD88 deficiency · MYD88D · pyogenic bacterial infections, recurrent, due to MyD88 deficiency · recurrent pyogenic bacterial infections due to MyD88 deficiency

Data availability: 161 ClinVar variants · 4 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 › pyogenic bacterial infections due to MyD88 deficiency

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, 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 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

161 retrieved; paginated sample, class counts are floors:

81 likely benign, 64 uncertain significance, 7 benign, 4 pathogenic, 2 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323304	NM_002468.5(MYD88):c.157G>T (p.Glu53Ter)	MYD88	Pathogenic	criteria provided, single submitter
2135205	NM_002468.5(MYD88):c.256_257del (p.Val86fs)	MYD88	Pathogenic	criteria provided, single submitter
235259	NM_002468.5(MYD88):c.154GAG[1] (p.Glu53del)	MYD88	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3246904	NC_000003.11:g.(?38180153)(38182777_?)del	MYD88	Pathogenic	criteria provided, single submitter
7496	NM_002468.5(MYD88):c.278T>C (p.Leu93Pro)	MYD88	Pathogenic	no assertion criteria provided
1508469	NM_002468.5(MYD88):c.463+1G>A	MYD88	Likely pathogenic	criteria provided, single submitter
1316463	NM_002468.5(MYD88):c.103_104del (p.Leu35fs)	MYD88	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469578	NM_002468.5(MYD88):c.-24_-6del	MYD88	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2424455	NC_000003.11:g.(?38180153)(38618292_?)dup	ACVR2B	Uncertain significance	criteria provided, single submitter
1002724	NM_002468.5(MYD88):c.328+6G>A	MYD88	Uncertain significance	criteria provided, single submitter
1004141	NM_002468.5(MYD88):c.602G>A (p.Gly201Asp)	MYD88	Uncertain significance	criteria provided, single submitter
1018824	NM_002468.5(MYD88):c.422C>G (p.Thr141Arg)	MYD88	Uncertain significance	criteria provided, single submitter
1021056	NM_002468.5(MYD88):c.455A>T (p.Asp152Val)	MYD88	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022664	NM_002468.5(MYD88):c.-39A>G	MYD88	Uncertain significance	criteria provided, single submitter
1046016	NM_002468.5(MYD88):c.500A>G (p.Tyr167Cys)	MYD88	Uncertain significance	criteria provided, multiple submitters, no conflicts
1052586	NM_002468.5(MYD88):c.-30G>T	MYD88	Uncertain significance	criteria provided, single submitter
1057053	NM_002468.5(MYD88):c.529G>A (p.Glu177Lys)	MYD88	Uncertain significance	criteria provided, single submitter
1345311	NM_002468.5(MYD88):c.62C>G (p.Pro21Arg)	MYD88	Uncertain significance	criteria provided, single submitter
134868	NM_002468.5(MYD88):c.121A>T (p.Thr41Ser)	MYD88	Uncertain significance	criteria provided, single submitter
134869	NM_002468.5(MYD88):c.-9C>G	MYD88	Uncertain significance	criteria provided, multiple submitters, no conflicts
1368280	NM_002468.5(MYD88):c.-26G>T	MYD88	Uncertain significance	criteria provided, single submitter
1372255	NM_002468.5(MYD88):c.573G>C (p.Leu191Phe)	MYD88	Uncertain significance	criteria provided, single submitter
1407259	NM_002468.5(MYD88):c.646T>A (p.Cys216Ser)	MYD88	Uncertain significance	criteria provided, multiple submitters, no conflicts
1414016	NM_002468.5(MYD88):c.322A>G (p.Ser108Gly)	MYD88	Uncertain significance	criteria provided, single submitter
1422697	NM_002468.5(MYD88):c.589G>A (p.Asp197Asn)	MYD88	Uncertain significance	criteria provided, single submitter
1430851	NM_002468.5(MYD88):c.838T>G (p.Cys280Gly)	MYD88	Uncertain significance	criteria provided, single submitter
1436032	NM_002468.5(MYD88):c.535A>G (p.Ile179Val)	MYD88	Uncertain significance	criteria provided, multiple submitters, no conflicts
1450408	NM_002468.5(MYD88):c.157G>A (p.Glu53Lys)	MYD88	Uncertain significance	criteria provided, single submitter
1469134	NM_002468.5(MYD88):c.115G>A (p.Val39Met)	MYD88	Uncertain significance	criteria provided, single submitter
1482715	NM_002468.5(MYD88):c.295G>A (p.Asp99Asn)	MYD88	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
MYD88	Strong	Autosomal recessive	pyogenic bacterial infections due to MyD88 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYD88	Orphanet:33226	Waldenström macroglobulinemia
MYD88	Orphanet:70592	Transient predisposition to invasive pyogenic bacterial infection
MYD88	Orphanet:714046	Primary choroidal lymphoma
ACVR2B	Orphanet:157769	Situs ambiguus

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
MYD88	HGNC:7562	ENSG00000172936	Q99836	Myeloid differentiation primary response protein MyD88	gencc,clinvar
ACVR2B	HGNC:174	ENSG00000114739	Q13705	Activin receptor type-2B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYD88	Myeloid differentiation primary response protein MyD88	Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response.
ACVR2B	Activin receptor type-2B	Transmembrane serine/threonine kinase activin type-2 receptor forming an activin receptor complex with activin type-1 serine/threonine kinase receptors (ACVR1, ACVR1B or ACVR1c).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYD88	Other/Unknown	no		TIR_dom, Death_dom, DEATH-like_dom_sf
ACVR2B	Kinase	yes		TGFB_receptor, Activin_recp, Prot_kinase_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
ganglionic eminence	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYD88	284	ubiquitous	marker	leukocyte, mononuclear cell, monocyte
ACVR2B	248	ubiquitous	marker	secondary oocyte, oocyte, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACVR2B	2,304
MYD88	404

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYD88	Q99836	14
ACVR2B	Q13705	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. 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
MyD88 deficiency (TLR5)	1	2855.0×	0.011	MYD88
IRAK4 deficiency (TLR5)	1	1427.5×	0.011	MYD88
p75NTR signals via NF-kB	1	951.7×	0.011	MYD88
DEx/H-box helicases activate type I IFN and inflammatory cytokines production	1	815.7×	0.011	MYD88
ZBP1(DAI) mediated induction of type I IFNs	1	519.1×	0.011	MYD88
Regulation of signaling by NODAL	1	475.8×	0.011	ACVR2B
p75NTR recruits signalling complexes	1	439.2×	0.011	MYD88
Diseases of Immune System	1	439.2×	0.011	MYD88
Diseases associated with the TLR signaling cascade	1	439.2×	0.011	MYD88
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling	1	439.2×	0.011	MYD88
Signaling by Activin	1	380.7×	0.012	ACVR2B
RIP-mediated NFkB activation via ZBP1	1	335.9×	0.012	MYD88
MyD88 deficiency (TLR2/4)	1	300.5×	0.012	MYD88
IRAK4 deficiency (TLR2/4)	1	285.5×	0.012	MYD88
Signaling by NODAL	1	248.3×	0.013	ACVR2B
Signaling by BMP	1	178.4×	0.017	ACVR2B
Antigen processing-Cross presentation	1	158.6×	0.018	MYD88
Cytosolic sensors of pathogen-associated DNA	1	142.8×	0.018	MYD88
Negative regulation of the PI3K/AKT network	1	139.3×	0.018	MYD88
Interleukin-1 family signaling	1	135.9×	0.018	MYD88
Toll Like Receptor 10 (TLR10) Cascade	1	107.7×	0.019	MYD88
Toll Like Receptor 5 (TLR5) Cascade	1	107.7×	0.019	MYD88
MyD88 cascade initiated on plasma membrane	1	102.0×	0.019	MYD88
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	95.2×	0.019	MYD88
MyD88 dependent cascade initiated on endosome	1	95.2×	0.019	MYD88
p75 NTR receptor-mediated signalling	1	93.6×	0.019	MYD88
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	92.1×	0.019	MYD88
Toll Like Receptor 9 (TLR9) Cascade	1	87.8×	0.019	MYD88
Toll Like Receptor TLR6:TLR2 Cascade	1	87.8×	0.019	MYD88
Toll Like Receptor 2 (TLR2) Cascade	1	86.5×	0.019	MYD88

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
response to molecule of fungal origin	1	8426.0×	0.004	MYD88
induced systemic resistance	1	8426.0×	0.004	MYD88
regulation of chemokine (C-X-C motif) ligand 1 production	1	8426.0×	0.004	MYD88
toll-like receptor 5 signaling pathway	1	4213.0×	0.005	MYD88
leukocyte activation involved in inflammatory response	1	2808.7×	0.005	MYD88
toll-like receptor 8 signaling pathway	1	2808.7×	0.005	MYD88
regulation of chemokine (C-X-C motif) ligand 2 production	1	2808.7×	0.005	MYD88
toll-like receptor TLR6:TLR2 signaling pathway	1	2106.5×	0.005	MYD88
neutrophil-mediated killing of bacterium	1	2106.5×	0.005	MYD88
regulation of neutrophil migration	1	2106.5×	0.005	MYD88
venous blood vessel development	1	1685.2×	0.005	ACVR2B
positive regulation of activin receptor signaling pathway	1	1404.3×	0.005	ACVR2B
Toll signaling pathway	1	1203.7×	0.005	MYD88
response to peptidoglycan	1	1203.7×	0.005	MYD88
positive regulation of interleukin-23 production	1	1203.7×	0.005	MYD88
lymphatic endothelial cell differentiation	1	1203.7×	0.005	ACVR2B
trophoblast cell migration	1	1203.7×	0.005	ACVR2B
negative regulation of adipose tissue development	1	1203.7×	0.005	ACVR2B
interleukin-33-mediated signaling pathway	1	1053.2×	0.005	MYD88
neutrophil activation involved in immune response	1	936.2×	0.005	MYD88
response to amine	1	936.2×	0.005	MYD88
positive regulation of lymphocyte proliferation	1	936.2×	0.005	MYD88
embryonic foregut morphogenesis	1	842.6×	0.005	ACVR2B
retina vasculature development in camera-type eye	1	842.6×	0.005	ACVR2B
microglia differentiation	1	766.0×	0.005	MYD88
artery development	1	702.2×	0.005	ACVR2B
establishment of endothelial intestinal barrier	1	702.2×	0.005	MYD88
cellular response to oxidised low-density lipoprotein particle stimulus	1	702.2×	0.005	MYD88
lymphangiogenesis	1	601.9×	0.006	ACVR2B
response to amino acid	1	495.6×	0.007	MYD88

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

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
ACVR2B	AXITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACVR2B	12	4
MYD88	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AXITINIB	4	ACVR2B
PAZOPANIB	4	ACVR2B
DASATINIB	4	ACVR2B
SARACATINIB	3	ACVR2B
ALVOCIDIB	3	ACVR2B
LESTAURTINIB	3	ACVR2B
VX-702	2	ACVR2B
TG100-801	2	ACVR2B
GSK-1070916	1	ACVR2B
KW-2449	1	ACVR2B
AZD-7762	1	ACVR2B
AST-487	1	ACVR2B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ACVR2B	104	Binding:104
MYD88	26	Binding:26

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ACVR2B	104

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

12 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)
AXITINIB	4	ACVR2B
PAZOPANIB	4	ACVR2B
DASATINIB	4	ACVR2B
SARACATINIB	3	ACVR2B
ALVOCIDIB	3	ACVR2B
LESTAURTINIB	3	ACVR2B
VX-702	2	ACVR2B
TG100-801	2	ACVR2B
GSK-1070916	1	ACVR2B
KW-2449	1	ACVR2B
AZD-7762	1	ACVR2B
AST-487	1	ACVR2B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ACVR2B
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	1	MYD88

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)
MYD88	26	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.