X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency

Summary

X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency (MONDO:0010389) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency
Mondo ID	MONDO:0010389
MeSH	C567068
OMIM	300645
Orphanet	319623
DOID	DOID:0112000
UMLS	C1970859
MedGen	370369
GARD	0017465
Is cancer (heuristic)	no

Also known as: CYBB X-linked mendelian susceptibility to mycobacterial diseases · IMD34 · immunodeficiency 34 · immunodeficiency 34, mycobacteriosis, X-linked, X-linked recessive · immunodeficiency type 34 · X-linked mendelian susceptibility to mycobacterial diseases caused by mutation in CYBB

Data availability: 12 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › inherited susceptibility to mycobacterial diseases › X-linked Mendelian susceptibility to mycobacterial diseases › X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency

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:

4 uncertain significance, 3 pathogenic, 2 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
10933	NM_000397.4(CYBB):c.252G>A (p.Ala84=)	CYBB	Pathogenic	criteria provided, multiple submitters, no conflicts
29969	NM_000397.4(CYBB):c.692A>C (p.Gln231Pro)	CYBB	Pathogenic	no assertion criteria provided
29970	NM_000397.4(CYBB):c.532A>C (p.Thr178Pro)	CYBB	Pathogenic	no assertion criteria provided
418153	NM_000397.4(CYBB):c.1662dup (p.Glu555Ter)	CYBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3598275	NM_000397.4(CYBB):c.667_668delinsTT (p.Gly223Leu)	CYBB	Likely pathogenic	criteria provided, single submitter
625929	NM_000397.4(CYBB):c.969A>G (p.Gln323=)	CYBB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732210	NM_000397.4(CYBB):c.1414G>A (p.Gly472Ser)	CYBB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1505442	NM_000397.4(CYBB):c.772C>G (p.Pro258Ala)	CYBB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584605	NM_000397.4(CYBB):c.728T>C (p.Val243Ala)	CYBB	Uncertain significance	criteria provided, single submitter
643505	NM_000397.4(CYBB):c.662T>C (p.Ile221Thr)	CYBB	Uncertain significance	criteria provided, multiple submitters, no conflicts
965223	NM_000397.4(CYBB):c.1291G>A (p.Ala431Thr)	CYBB	Uncertain significance	criteria provided, multiple submitters, no conflicts
68372	NM_000397.4(CYBB):c.1090G>C (p.Gly364Arg)	CYBB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
CYBB	Definitive	X-linked	granulomatous disease, chronic, X-linked	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYBB	Orphanet:319605	X-linked mendelian susceptibility to mycobacterial diseases
CYBB	Orphanet:379	Chronic granulomatous disease

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
CYBB	HGNC:2578	ENSG00000165168	P04839	NADPH oxidase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYBB	NADPH oxidase 2	Catalytic subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYBB	Other/Unknown	no		Cyt_b245_heavy_chain, FAD-bd_8, Fe_red_NAD-bd_6

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
CYBB	246	broad	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYBB	4,117

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYBB	P04839	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Cross-presentation of particulate exogenous antigens (phagosomes)	1	1427.5×	0.006	CYBB
RHO GTPases Activate NADPH Oxidases	1	456.8×	0.007	CYBB
ROS and RNS production in phagocytes	1	335.9×	0.007	CYBB
Detoxification of Reactive Oxygen Species	1	300.5×	0.007	CYBB
VEGFA-VEGFR2 Pathway	1	139.3×	0.011	CYBB
RAC2 GTPase cycle	1	126.9×	0.011	CYBB
RAC3 GTPase cycle	1	119.0×	0.011	CYBB
RAC1 GTPase cycle	1	61.1×	0.018	CYBB
Neutrophil degranulation	1	23.1×	0.043	CYBB

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
hypoxia-inducible factor-1alpha signaling pathway	1	4213.0×	0.002	CYBB
cellular response to L-glutamine	1	4213.0×	0.002	CYBB
response to angiotensin	1	1872.4×	0.002	CYBB
response to aldosterone	1	1685.2×	0.002	CYBB
hydrogen peroxide biosynthetic process	1	1404.3×	0.002	CYBB
respiratory burst	1	1296.3×	0.002	CYBB
cellular response to ethanol	1	1053.2×	0.002	CYBB
superoxide metabolic process	1	991.3×	0.002	CYBB
cellular response to cadmium ion	1	766.0×	0.003	CYBB
superoxide anion generation	1	674.1×	0.003	CYBB
response to nutrient	1	295.6×	0.006	CYBB
defense response	1	216.1×	0.007	CYBB
monoatomic ion transmembrane transport	1	208.1×	0.007	CYBB
positive regulation of tumor necrosis factor production	1	153.2×	0.008	CYBB
positive regulation of angiogenesis	1	115.4×	0.010	CYBB
response to xenobiotic stimulus	1	69.1×	0.016	CYBB
inflammatory response	1	37.7×	0.028	CYBB
innate immune response	1	33.6×	0.030	CYBB

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
CYBB	NALOXONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYBB	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NALOXONE	4	CYBB
EBSELEN	3	CYBB
SETANAXIB	2	CYBB
ISUZINAXIB	2	CYBB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CYBB	56	Binding:54, Unclassified:1, Functional:1

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

4 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)
NALOXONE	4	CYBB
EBSELEN	3	CYBB
SETANAXIB	2	CYBB
ISUZINAXIB	2	CYBB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYBB
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.