granulomatous disease, chronic, X-linked

Summary

granulomatous disease, chronic, X-linked (MONDO:0010600) is a disease caused by CYBB (GenCC Definitive), with 5 cohort genes and 6 clinical trials. Top therapeutic interventions include briquilimab.

At a glance

• Causal gene: CYBB (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 675
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	granulomatous disease, chronic, X-linked
Mondo ID	MONDO:0010600
MeSH	C564210
OMIM	138990, 306400
DOID	DOID:0070190, DOID:0070195
UMLS	C1844376
MedGen	336165
GARD	0015294
Is cancer (heuristic)	no

Also known as: CGD · chronic granulomatous disease, atypical · chronic granulomatous disease, X-linked · chronic granulomatous disease, X-linked, X-linked recessive · cytochrome B-negative granulomatous disease, chronic, X-linked · cytochrome B-positive granulomatous disease, chronic, X-linked · granulomatous disease, chronic, autosomal dominant type · granulomatous disease, chronic, X-linked · granulomatous disease, chronic, X-linked, variant

Data availability: 675 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › chronic granulomatous disease › granulomatous disease, chronic, X-linked

Related subtypes (6): granulomatous disease with defect in neutrophil chemotaxis, granulomatous disease, chronic, autosomal recessive, cytochrome b-negative, granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1, granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2, granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3, granulomatous disease, chronic, autosomal recessive, 5

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

600 retrieved; paginated sample, class counts are floors:

269 likely benign, 123 uncertain significance, 119 pathogenic, 31 benign, 27 likely pathogenic, 15 conflicting classifications of pathogenicity, 9 benign/likely benign, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012317	NM_000397.4(CYBB):c.752G>A (p.Trp251Ter)	CYBB	Pathogenic	criteria provided, single submitter
1012321	NM_000397.4(CYBB):c.190T>C (p.Cys64Arg)	CYBB	Pathogenic	criteria provided, single submitter
1012323	NM_000397.4(CYBB):c.1271G>A (p.Trp424Ter)	CYBB	Pathogenic	criteria provided, single submitter
1048546	NM_000397.4(CYBB):c.-65C>G	CYBB	Pathogenic	no assertion criteria provided
1068155	NM_000397.4(CYBB):c.1673del (p.Pro558fs)	CYBB	Pathogenic	criteria provided, single submitter
1070320	NM_000397.4(CYBB):c.483+1G>A	CYBB	Pathogenic	criteria provided, multiple submitters, no conflicts
1070694	NM_000397.4(CYBB):c.565del (p.Ile189fs)	CYBB	Pathogenic	criteria provided, single submitter
1071577	NM_000397.4(CYBB):c.675-2A>G	CYBB	Pathogenic	criteria provided, single submitter
1071578	NM_000397.4(CYBB):c.1151+1G>A	CYBB	Pathogenic	criteria provided, single submitter
1072432	NM_000397.4(CYBB):c.1314+1G>A	CYBB	Pathogenic	criteria provided, single submitter
1074313	NM_000397.4(CYBB):c.1519C>T (p.Gln507Ter)	CYBB	Pathogenic	criteria provided, single submitter
1074314	NM_000397.4(CYBB):c.1645C>T (p.Gln549Ter)	CYBB	Pathogenic	criteria provided, single submitter
1074351	NM_000397.4(CYBB):c.46-2A>T	CYBB	Pathogenic	criteria provided, single submitter
1076169	NM_000397.4(CYBB):c.603C>G (p.Tyr201Ter)	CYBB	Pathogenic	criteria provided, single submitter
1076290	NM_000397.4(CYBB):c.3G>A (p.Met1Ile)	CYBB	Pathogenic	criteria provided, single submitter
10920	NM_000397.4(CYBB):c.1244C>A (p.Pro415His)	CYBB	Pathogenic	criteria provided, multiple submitters, no conflicts
10923	NM_000397.4(CYBB):c.217C>T (p.Arg73Ter)	CYBB	Pathogenic	criteria provided, multiple submitters, no conflicts
10925	NM_000397.4(CYBB):c.466G>A (p.Ala156Thr)	CYBB	Pathogenic	criteria provided, single submitter
10926	NM_000397.4(CYBB):c.302A>G (p.His101Arg)	CYBB	Pathogenic	criteria provided, single submitter
10927	NM_000397.4(CYBB):c.911C>G (p.Pro304Arg)	CYBB	Pathogenic	no assertion criteria provided
10928	NM_000397.4(CYBB):c.1462-2A>G	CYBB	Pathogenic	no assertion criteria provided
10929	NM_000397.4(CYBB):c.676C>T (p.Arg226Ter)	CYBB	Pathogenic	criteria provided, multiple submitters, no conflicts
10930	NM_000397.4(CYBB):c.252+5G>A	CYBB	Pathogenic	criteria provided, single submitter
10931	NM_000397.4(CYBB):c.1499A>G (p.Asp500Gly)	CYBB	Pathogenic	criteria provided, single submitter
10933	NM_000397.4(CYBB):c.252G>A (p.Ala84=)	CYBB	Pathogenic	criteria provided, multiple submitters, no conflicts
10934	NM_000397.4:c.484-262_484-261insLINE1	CYBB	Pathogenic	no assertion criteria provided
10937	NM_000397.4(CYBB):c.483+979G>T	CYBB	Pathogenic	no assertion criteria provided
10938	NG_009065.1:g.16964_16965insLINE1	CYBB	Pathogenic	no assertion criteria provided
10940	NM_000397.4(CYBB):c.90_92delinsGGT (p.Tyr30_Arg31delinsTer)	CYBB	Pathogenic	no assertion criteria provided
1196543	NM_000397.4(CYBB):c.1A>G (p.Met1Val)	CYBB	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
XK	Orphanet:59306	McLeod neuroacanthocytosis syndrome
CYBA	Orphanet:379	Chronic granulomatous disease
G6PD	Orphanet:466026	Class I glucose-6-phosphate dehydrogenase deficiency
OTC	Orphanet:664	Ornithine transcarbamylase deficiency

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYBB	HGNC:2578	ENSG00000165168	P04839	NADPH oxidase 2	gencc,clinvar
XK	HGNC:12811	ENSG00000047597	P51811	Endoplasmic reticulum membrane adapter protein XK	clinvar
CYBA	HGNC:2577	ENSG00000051523	P13498	Cytochrome b-245 light chain	clinvar
G6PD	HGNC:4057	ENSG00000160211	P11413	Glucose-6-phosphate 1-dehydrogenase	clinvar
OTC	HGNC:8512	ENSG00000036473	P00480	Ornithine transcarbamylase, mitochondrial	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(-)).
XK	Endoplasmic reticulum membrane adapter protein XK	Recruits the lipid transfer protein VPS13A from lipid droplets to the endoplasmic reticulum (ER) membrane.
CYBA	Cytochrome b-245 light chain	Subunit of NADPH oxidase complexes that is required for the NADPH oxidase activity that generates, in various cell types, superoxide from molecular oxygen utilizing NADPH as an electron donor.
G6PD	Glucose-6-phosphate 1-dehydrogenase	Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis.
OTC	Ornithine transcarbamylase, mitochondrial	Catalyzes the second step of the urea cycle, the condensation of carbamoyl phosphate with L-ornithine to form L-citrulline.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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
Enzyme (other)	2	4.8×	0.117
Other/Unknown	3	1.1×	0.608

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
XK	Other/Unknown	no		XK-rel, XK-related_adapter
CYBA	Other/Unknown	no		Cyt_b558_asu
G6PD	Enzyme (other)	yes	1.1.1.49	G6P_DH, G6P_DH_AS, G6P_DH_NAD-bd
OTC	Enzyme (other)	yes	2.1.3.3	Orn/put_carbamltrans, Asp/Orn_carbamoylTrfase, Asp_carbamoyltransf_Asp/Orn-bd

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	2
monocyte	2
jejunal mucosa	2
granulocyte	2
mononuclear cell	1
colonic mucosa	1
trabecular bone tissue	1
right testis	1
stromal cell of endometrium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYBB	246	broad	marker	monocyte, mononuclear cell, leukocyte
XK	221	broad	marker	trabecular bone tissue, jejunal mucosa, colonic mucosa
CYBA	267	ubiquitous	marker	granulocyte, monocyte, leukocyte
G6PD	218	ubiquitous	marker	stromal cell of endometrium, granulocyte, right testis
OTC	139	tissue_specific	marker	jejunal mucosa, right lobe of liver, liver

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
G6PD	4,226
CYBB	4,117
OTC	2,513
CYBA	1,699
XK	697

Intra-cohort edges

A	B	Sources
CYBA	CYBB	biogrid_interaction, intact, string_interaction
CYBA	XK	string_interaction
CYBB	XK	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
G6PD	P11413	25
CYBA	P13498	7
CYBB	P04839	6
OTC	P00480	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
XK	P51811	81.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 5 evidence-associated genes (5 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 5 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)	2	571.0×	8e-05	CYBB, CYBA
RHO GTPases Activate NADPH Oxidases	2	182.7×	4e-04	CYBB, CYBA
ROS and RNS production in phagocytes	2	134.3×	5e-04	CYBB, CYBA
Detoxification of Reactive Oxygen Species	2	120.2×	5e-04	CYBB, CYBA
OTC leader sequence variants cause OTC deficiency	1	2284.0×	0.001	OTC
OTC main chain variants cause OTC deficiency	1	2284.0×	0.001	OTC
VEGFA-VEGFR2 Pathway	2	55.7×	0.001	CYBB, CYBA
RAC2 GTPase cycle	2	50.8×	0.001	CYBB, CYBA
RAC3 GTPase cycle	2	47.6×	0.001	CYBB, CYBA
RAC1 GTPase cycle	2	24.4×	0.005	CYBB, CYBA
NFE2L2 regulates pentose phosphate pathway genes	1	285.5×	0.006	G6PD
Pentose phosphate pathway	1	190.3×	0.007	G6PD
WNT5:FZD7-mediated leishmania damping	1	190.3×	0.007	CYBA
Urea cycle	1	175.7×	0.007	OTC
Neutrophil degranulation	2	9.2×	0.021	CYBB, CYBA
Mitochondrial protein import	1	33.6×	0.033	OTC
TP53 Regulates Metabolic Genes	1	25.9×	0.040	G6PD
Peptide ligand-binding receptors	1	14.8×	0.066	XK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to L-glutamine	2	1685.2×	3e-05	CYBB, CYBA
response to aldosterone	2	674.1×	1e-04	CYBB, CYBA
hydrogen peroxide biosynthetic process	2	561.7×	1e-04	CYBB, CYBA
respiratory burst	2	518.5×	1e-04	CYBB, CYBA
superoxide metabolic process	2	396.5×	2e-04	CYBB, CYBA
superoxide anion generation	2	269.6×	3e-04	CYBB, CYBA
response to xenobiotic stimulus	3	41.4×	3e-04	CYBB, CYBA, OTC
negative regulation of glomerular filtration by angiotensin	1	3370.4×	0.002	CYBA
L-ornithine catabolic process	1	3370.4×	0.002	OTC
smooth muscle hypertrophy	1	3370.4×	0.002	CYBA
ribose phosphate biosynthetic process	1	3370.4×	0.002	G6PD
response to iron(III) ion	1	1685.2×	0.003	G6PD
cytochrome complex assembly	1	1685.2×	0.003	CYBA
pentose biosynthetic process	1	1685.2×	0.003	G6PD
obsolete L-arginine biosynthetic process via ornithine	1	1685.2×	0.003	OTC
monoatomic anion homeostasis	1	1685.2×	0.003	OTC
response to biotin	1	1685.2×	0.003	OTC
positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	1685.2×	0.003	G6PD
positive regulation of tumor necrosis factor production	2	61.3×	0.003	CYBB, CYBA
pentose-phosphate shunt, oxidative branch	1	842.6×	0.004	G6PD
L-citrulline biosynthetic process	1	842.6×	0.004	OTC
hypoxia-inducible factor-1alpha signaling pathway	1	842.6×	0.004	CYBB
regulation of axon diameter	1	674.1×	0.005	XK
positive regulation of mucus secretion	1	674.1×	0.005	CYBA
intracellular magnesium ion homeostasis	1	561.7×	0.006	XK
ammonium homeostasis	1	481.5×	0.007	OTC
midgut development	1	421.3×	0.007	OTC
positive regulation of toll-like receptor 2 signaling pathway	1	421.3×	0.007	CYBA
positive regulation of defense response to bacterium	1	374.5×	0.007	CYBA
response to angiotensin	1	374.5×	0.007	CYBB

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
G6PD	BREXANOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
G6PD	8	4
CYBB	4	4
XK	0	0
CYBA	0	0
OTC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NALOXONE	4	CYBB
BREXANOLONE	4	G6PD
APOMORPHINE HYDROCHLORIDE	4	G6PD
PRASTERONE	4	G6PD
EBSELEN	3	CYBB, G6PD
SETANAXIB	2	CYBB
ISUZINAXIB	2	CYBB
PICEID	2	G6PD
SEPRANOLONE	2	G6PD
PREGNENOLONE	1	G6PD
16.ALPHA.-BROMOEPIANDROSTERONE	1	G6PD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CYBB	56	Binding:54, Unclassified:1, Functional:1
G6PD	49	Binding:46, ADMET:2, Functional:1
OTC	3	Binding:3
CYBA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
G6PD	1.1.1.49	glucose-6-phosphate dehydrogenase (NADP+)
OTC	2.1.3.3	ornithine carbamoyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
G6PD	1

Chemical tractability of cohort targets

11 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
BREXANOLONE	4	G6PD
APOMORPHINE HYDROCHLORIDE	4	G6PD
PRASTERONE	4	G6PD
EBSELEN	3	CYBB, G6PD
SETANAXIB	2	CYBB
ISUZINAXIB	2	CYBB
PICEID	2	G6PD
SEPRANOLONE	2	G6PD
PREGNENOLONE	1	G6PD
16.ALPHA.-BROMOEPIANDROSTERONE	1	G6PD

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CYBB, G6PD
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	OTC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	XK, CYBA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
XK	0	CYBB
CYBA	1	CYBB
OTC	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1/PHASE2	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01381003	PHASE1/PHASE2	WITHDRAWN	Lentiviral Gene Therapy for X-Linked Chronic Granulomatous Disease (X-CGD)
NCT02234934	PHASE1/PHASE2	COMPLETED	Study of Gene Therapy Using a Lentiviral Vector to Treat X-linked Chronic Granulomatous Disease
NCT05600907	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Study to Assess the Use of JSP191 in Matched Unrelated Donor Transplantation for Chronic Granulomatous Disease (CGD)
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02233036	Not specified	COMPLETED	Evaluating the Transition From Pediatric to Adult Care Among Adolescents With Chronic Granulomatous Disease
NCT05546775	Not specified	UNKNOWN	Immunological Profile and Clinical Characteristics of Children Diagnosed With Chronic Granulomatous Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BRIQUILIMAB	2	1