Cryptococcosis

Summary

Cryptococcosis (MONDO:0005724) is a disease with 8 cohort genes (8 GWAS associations across 1 studies) and 14 clinical trials. Top therapeutic interventions include fluconazole, itraconazole, and voriconazole.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 8
• GWAS associations: 8
• Phenotypes (HPO): 42
• Clinical trials: 14

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-5 / 10 000	11	Europe	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0001945	Fever	Frequent (30-79%)
HP:0002721	Immunodeficiency	Frequent (30-79%)
HP:0012735	Cough	Frequent (30-79%)
HP:0025392	Nodular pattern on pulmonary HRCT	Frequent (30-79%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000478	Abnormality of the eye	Occasional (5-29%)
HP:0000504	Abnormality of vision	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001287	Meningitis	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002202	Pleural effusion	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002516	Increased intracranial pressure	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0002725	Systemic lupus erythematosus	Occasional (5-29%)
HP:0002960	Autoimmunity	Occasional (5-29%)
HP:0003690	Limb muscle weakness	Occasional (5-29%)
HP:0031179	Nuchal rigidity	Occasional (5-29%)
HP:0100721	Mediastinal lymphadenopathy	Occasional (5-29%)
HP:0100749	Chest pain	Occasional (5-29%)
HP:0000024	Prostatitis	Very rare (<1-4%)
HP:0000356	Abnormality of the outer ear	Very rare (<1-4%)
HP:0000479	Abnormal retinal morphology	Very rare (<1-4%)
HP:0000587	Abnormal optic nerve morphology	Very rare (<1-4%)
HP:0000602	Ophthalmoplegia	Very rare (<1-4%)
HP:0000618	Blindness	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001291	Abnormal cranial nerve morphology	Very rare (<1-4%)
HP:0002181	Cerebral edema	Very rare (<1-4%)
HP:0002354	Memory impairment	Very rare (<1-4%)
HP:0002586	Peritonitis	Very rare (<1-4%)
HP:0002754	Osteomyelitis	Very rare (<1-4%)
HP:0002797	Osteolysis	Very rare (<1-4%)
HP:0005526	Lymphoid leukemia	Very rare (<1-4%)
HP:0011531	Vitritis	Very rare (<1-4%)
HP:0100806	Sepsis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cryptococcosis
Mondo ID	MONDO:0005724
EFO	EFO:0007229
MeSH	D003453
Orphanet	1546
DOID	DOID:12053
ICD-10-CM	B45
ICD-11	390527954
NCIT	C2967
SNOMED CT	42386007
UMLS	C0010414
MedGen	8189
GARD	0006218
MedDRA	10011490
NORD	1019
Is cancer (heuristic)	no

Also known as: Cryptococcus neoformans caused disease or disorder · Cryptococcus neoformans disease or disorder · Cryptococcus neoformans infectious disease · torulosis

Data availability: 8 GWAS associations (1 study).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of primarily extrinsic mechanism › infectious disease › fungal infectious disease › opportunistic mycosis › cryptococcosis

Related subtypes (11): phaeohyphomycosis, candidiasis, maple bark strippers’ lung, aspergillosis, geotrichosis, microsporidiosis, fusariosis, pneumocystosis, Zygomycosis, opportunistic systemic mycosis, hyalohyphomycosis

Subtypes (1): Cryptococcal meningitis

Genetics & variants

GWAS landscape

8 GWAS associations across 1 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1999714	3e-07	LINC01768 - CSF1	?	0.67
rs4933565	1e-06	LINC00865	?	1.64
rs28445794	4e-06	RNU6-1 - PIAS1	?	0.93
rs3128900	5e-06	POLR1HASP, POLR1HASP	?	0.97
rs114228467	7e-06	JMY - HOMER1	?	3.25
rs61126502	8e-06	MCM3 - PAQR8	?	1.06
rs273465	8e-06	KRT18P24 - CHCHD2P9	?	0.91
rs2394251	9e-06	HCG9, POLR1HASP, POLR1HASP	?	0.74

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST011681	Kannambath S	2020	319	0	Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	2
Tier 4: intronic/intergenic	6

MAF distribution

Bucket	Variants
common (>=0.05)	6
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	2

Functional consequences

Consequence	Count
intergenic_variant	3
intron_variant	3
regulatory_region_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1999714	1	109907411	G>A,C,T	0.05	intergenic_variant	LINC01768 - CSF1	3e-07	Tier 4: intronic/intergenic
rs4933565	10	90177983	G>A,C,T	0.05	intron_variant	LINC00865	1e-06	Tier 4: intronic/intergenic
rs28445794	15	67889916	T>A,C,G	0.05	intergenic_variant	RNU6-1 - PIAS1	4e-06	Tier 4: intronic/intergenic
rs3128900	6	29865280	G>C,T	0.05	intron_variant	POLR1HASP, POLR1HASP	5e-06	Tier 4: intronic/intergenic
rs114228467	5	79342896	G>A		intergenic_variant	JMY - HOMER1	7e-06	Tier 4: intronic/intergenic
rs61126502	6	52297617	C>T		regulatory_region_variant	MCM3 - PAQR8	8e-06	Tier 3: regulatory
rs273465	9	79220822	C>A	0.05	regulatory_region_variant	KRT18P24 - CHCHD2P9	8e-06	Tier 3: regulatory
rs2394251	6	29975911	G>A,C,T	0.05	intron_variant	HCG9, POLR1HASP, POLR1HASP	9e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL17F	Orphanet:1334	Chronic mucocutaneous candidiasis

Cohort genes → proteins

8 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNU6-1	HGNC:10227	ENSG00000206625		RNA, U6 small nuclear 1	gwas
IL17F	HGNC:16404	ENSG00000112116	Q96PD4	Interleukin-17F	gwas
HOMER1	HGNC:17512	ENSG00000152413	Q86YM7	Homer protein homolog 1	gwas
CSF1	HGNC:2432	ENSG00000184371	P09603	Macrophage colony-stimulating factor 1	gwas
JMY	HGNC:28916	ENSG00000152409	Q8N9B5	Junction-mediating and -regulatory protein	gwas
HLA-H	HGNC:4965	ENSG00000206341	P01893	Putative HLA class I histocompatibility antigen, alpha chain H	gwas
LINC01375	HGNC:50632	ENSG00000226159		long intergenic non-protein coding RNA 1375	gwas
MCM3	HGNC:6945	ENSG00000112118	P25205	DNA replication licensing factor MCM3	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL17F	Interleukin-17F	Effector cytokine of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity.
HOMER1	Homer protein homolog 1	Postsynaptic density scaffolding protein.
CSF1	Macrophage colony-stimulating factor 1	Cytokine that plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes.
JMY	Junction-mediating and -regulatory protein	Acts both as a nuclear p53/TP53-cofactor and a cytoplasmic regulator of actin dynamics depending on conditions.
HLA-H	Putative HLA class I histocompatibility antigen, alpha chain H	Involved in the presentation of foreign antigens to the immune system.
MCM3	DNA replication licensing factor MCM3	Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.12

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	7	1.6×	0.138
Antibody/Immunoglobulin	1	3.6×	0.243

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNU6-1	Other/Unknown	no
IL17F	Other/Unknown	no		IL-17_fam, IL-17_chr, Cystine-knot_cytokine
HOMER1	Other/Unknown	no		WH1/EVH1_dom, PH-like_dom_sf, Homer_EVH1
CSF1	Other/Unknown	no		MCSF-1, 4_helix_cytokine-like_core
JMY	Other/Unknown	no		WH2_dom, JMY/WHAMM, JMY/WHAMM_N
HLA-H	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig/MHC_CS, Ig_C1-set
LINC01375	Other/Unknown	no
MCM3	Other/Unknown	no		MCM_dom, AAA+_ATPase, Mcm3

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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	2
male germ line stem cell (sensu Vertebrata) in testis	2
adrenal tissue	1
corpus callosum	1
sural nerve	1
primordial germ cell in gonad	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
orbitofrontal cortex	1
adipose tissue of abdominal region	1
omental fat pad	1
peritoneum	1
oocyte	1
sperm	1
blood	1
granulocyte	1
stromal cell of endometrium	1
bone marrow cell	1
pancreas	1
embryo	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNU6-1	117	broad	yes	sural nerve, adrenal tissue, corpus callosum
IL17F	43		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, endothelial cell
HOMER1	293	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, orbitofrontal cortex
CSF1	223	ubiquitous	marker	omental fat pad, peritoneum, adipose tissue of abdominal region
JMY	254	ubiquitous	marker	endothelial cell, sperm, oocyte
HLA-H	133		marker	granulocyte, stromal cell of endometrium, blood
LINC01375	31		yes	male germ line stem cell (sensu Vertebrata) in testis, pancreas, bone marrow cell
MCM3	283	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCM3	3,953
CSF1	3,476
HOMER1	2,073
IL17F	1,523
JMY	1,130
HLA-H	23
RNU6-1	0
LINC01375	0

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCM3	P25205	28
IL17F	Q96PD4	9
CSF1	P09603	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HLA-H	P01893	88.82
HOMER1	Q86YM7	87.47
JMY	Q8N9B5	66.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 8 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DNA strand elongation	1	190.3×	0.061	MCM3
Unwinding of DNA	1	146.4×	0.061	MCM3
Regulation of TP53 Activity through Methylation	1	90.6×	0.061	JMY
Other interleukin signaling	1	79.3×	0.061	CSF1
Signaling by CSF1 (M-CSF) in myeloid cells	1	57.7×	0.061	CSF1
Activation of the pre-replicative complex	1	54.4×	0.061	MCM3
DNA Replication Pre-Initiation	1	52.9×	0.061	MCM3
Activation of ATR in response to replication stress	1	50.1×	0.061	MCM3
Switching of origins to a post-replicative state	1	50.1×	0.061	MCM3
Synthesis of DNA	1	50.1×	0.061	MCM3
Interleukin-17 signaling	1	42.3×	0.061	IL17F
DNA Replication	1	39.6×	0.061	MCM3
Interleukin-10 signaling	1	38.8×	0.061	CSF1
G1/S Transition	1	38.8×	0.061	MCM3
Neurexins and neuroligins	1	32.8×	0.061	HOMER1
Mitotic G1 phase and G1/S transition	1	30.7×	0.061	MCM3
S Phase	1	30.2×	0.061	MCM3
Orc1 removal from chromatin	1	29.7×	0.061	MCM3
Transcriptional and post-translational regulation of MITF-M expression and activity	1	29.7×	0.061	CSF1
Interferon alpha/beta signaling	1	25.4×	0.067	HLA-H
Assembly of the pre-replicative complex	1	23.2×	0.067	MCM3
G2/M Checkpoints	1	22.4×	0.067	MCM3
Regulation of TP53 Activity	1	22.1×	0.067	JMY
Interferon gamma signaling	1	20.9×	0.068	HLA-H
Interleukin-4 and Interleukin-13 signaling	1	17.1×	0.079	IL17F
Post-translational protein phosphorylation	1	16.7×	0.079	CSF1
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	14.9×	0.081	IL17F
Cell Cycle Checkpoints	1	14.8×	0.081	MCM3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	14.4×	0.081	CSF1
Transcriptional Regulation by TP53	1	10.3×	0.108	JMY

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of macrophage derived foam cell differentiation	1	2808.7×	0.006	CSF1
regulation of granulocyte macrophage colony-stimulating factor production	1	2808.7×	0.006	IL17F
mammary gland fat development	1	2808.7×	0.006	CSF1
‘de novo’ actin filament nucleation	1	2808.7×	0.006	JMY
positive regulation of macrophage colony-stimulating factor signaling pathway	1	2808.7×	0.006	CSF1
positive regulation of antimicrobial peptide production	1	1404.3×	0.007	IL17F
regulation of interleukin-2 production	1	1404.3×	0.007	IL17F
positive regulation of odontogenesis of dentin-containing tooth	1	1404.3×	0.007	CSF1
positive regulation of lymphotoxin A production	1	936.2×	0.007	IL17F
monocyte homeostasis	1	936.2×	0.007	CSF1
macrophage colony-stimulating factor signaling pathway	1	936.2×	0.007	CSF1
mammary duct terminal end bud growth	1	936.2×	0.007	CSF1
macrophage homeostasis	1	936.2×	0.007	CSF1
positive regulation of macrophage migration	1	936.2×	0.007	CSF1
phospholipase C-activating G protein-coupled glutamate receptor signaling pathway	1	702.2×	0.007	HOMER1
regulation of interleukin-8 production	1	702.2×	0.007	IL17F
positive regulation of mononuclear cell proliferation	1	702.2×	0.007	CSF1
myeloid leukocyte migration	1	702.2×	0.007	CSF1
regulation of dendritic spine maintenance	1	702.2×	0.007	HOMER1
osteoclast proliferation	1	561.7×	0.008	CSF1
developmental process involved in reproduction	1	561.7×	0.008	CSF1
mitotic DNA replication initiation	1	468.1×	0.008	MCM3
positive regulation of microglial cell migration	1	468.1×	0.008	CSF1
positive regulation of chemokine (C-X-C motif) ligand 1 production	1	468.1×	0.008	IL17F
actin polymerization-dependent cell motility	1	401.2×	0.009	JMY
regulation of calcium ion import	1	351.1×	0.010	HOMER1
DNA strand elongation involved in DNA replication	1	312.1×	0.010	MCM3
monocyte activation	1	312.1×	0.010	CSF1
microglial cell proliferation	1	312.1×	0.010	CSF1
regulation of interleukin-6 production	1	280.9×	0.010	IL17F

Therapeutics

Drugs indicated for this disease

1 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Amphotericin B	Approved (phase 4)
Itraconazole	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 8

Druggability breadth: 3 of 8 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RNU6-1	0	0
IL17F	0	0
HOMER1	0	0
CSF1	0	0
JMY	0	0
HLA-H	0	0
LINC01375	0	0
MCM3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MCM3	10	Binding:10
IL17F	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	HLA-H
E	Difficult family or no structure, no drug	7	RNU6-1, IL17F, HOMER1, CSF1, JMY, LINC01375, MCM3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNU6-1	0	—
IL17F	2	—
HOMER1	0	—
CSF1	0	—
JMY	0	—
HLA-H	0	—
LINC01375	0	—
MCM3	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 14.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE3	3
PHASE4	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00647907	PHASE4	COMPLETED	A Study of the Efficacy and Safety of Voriconazole for the Treatment of Fungal Infections
NCT01535469	PHASE4	COMPLETED	Operational Research for Cryptococcal Antigen Screening
NCT00784368	PHASE3	COMPLETED	A Pharmacokinetic Study of JK1211(Itraconazole [Itrizole]) Oral Solution in Participants With Deep Mycosis and Those With Febrile Neutropenia Suspected of Fungal Infection
NCT01125644	PHASE3	UNKNOWN	Efficacy, Safety and Pharmacokinetics of SPK-843 in the Treatment of Pulmonary Mycosis
NCT03002012	PHASE3	TERMINATED	Cryptococcal Antigen Screening Plus Sertraline
NCT00001352	Not specified	RECRUITING	Fungal Infection Susceptibility
NCT02454569	Not specified	RECRUITING	Vicente Ferrer HIV Cohort Study
NCT00001701	Not specified	COMPLETED	Evaluation of the Association of Polymorphisms in the Innate Immune System With the Risk for Cryptococcus Neoformans Infection in Patients Not Infected With HIV and Complications Associated With Cryptococcus Neoformans Infection
NCT02503449	Not specified	UNKNOWN	Clinical Trial of Pulmonary Cryptococcosis in China
NCT03267407	Not specified	UNKNOWN	Vietnam Cryptococcal Retention in Care Study - Version 2.1
NCT03993093	Not specified	COMPLETED	Prevalence of HIV +ve Cases With AIDS Defining Opportunistic Infections Among ART Naive Patients Attending ART Centre
NCT04033718	Not specified	COMPLETED	Inpatient Package to Reduce HIV and AIDS-related Death in Zambia
NCT04554875	Not specified	UNKNOWN	Derivation and Validation of a Scoring System to Distinguish Cryptococcosis and Adenocarcinoma in Pulmonary Nodules
NCT05707156	Not specified	COMPLETED	Prospective Observational Study on the Incidence of Opportunistic Fungal Infections

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUCONAZOLE	4	2
ITRACONAZOLE	4	1
VORICONAZOLE	4	1
AMCIPATRICIN DIASCORBATE	3	1