Caroli disease

Summary

Caroli disease (MONDO:0010913) is a disease caused by PKD1 (GenCC Strong), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: PKD1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 7
• Phenotypes (HPO): 33
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.1	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0001396	Cholestasis	Very frequent (80-99%)
HP:0000952	Jaundice	Frequent (30-79%)
HP:0001406	Intrahepatic cholestasis	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002908	Conjugated hyperbilirubinemia	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Frequent (30-79%)
HP:0030151	Cholangitis	Frequent (30-79%)
HP:0030948	Elevated gamma-glutamyltransferase level	Frequent (30-79%)
HP:0000113	Polycystic kidney dysplasia	Occasional (5-29%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0001081	Cholelithiasis	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0001541	Ascites	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0001974	Leukocytosis	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0002040	Esophageal varix	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0025143	Chills	Occasional (5-29%)
HP:0031964	Elevated circulating alanine aminotransferase concentration	Occasional (5-29%)
HP:0032106	Conjunctival icterus	Occasional (5-29%)
HP:0032545	Abdominal rigidity	Occasional (5-29%)
HP:0001405	Periportal fibrosis	Excluded (0%)
HP:0045056	Abnormal levels of alpha-fetoprotein	Excluded (0%)
HP:0001395	Hepatic fibrosis	Very rare (<1-4%)
HP:0001409	Portal hypertension	Very rare (<1-4%)
HP:0002613	Biliary cirrhosis	Very rare (<1-4%)
HP:0030153	Cholangiocarcinoma	Very rare (<1-4%)
HP:0100523	Liver abscess	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Caroli disease
Mondo ID	MONDO:0010913
EFO	EFO:1001286
MeSH	D016767
OMIM	600643
Orphanet	53035
DOID	DOID:0050876
ICD-11	1757434239
NCIT	C84619
SNOMED CT	717232005
UMLS	C0162510
MedGen	57924
GARD	0006002
MedDRA	10013003
NORD	896
Is cancer (heuristic)	no

Also known as: Caroli disease isolated · congenital polycystic dilatation of intrahepatic bile ducts · cystic dilatation of the intrahepatic biliary tree

Data availability: 7 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › biliary tract disorder › bile duct disorder › non-neoplastic bile duct disorder › Caroli disease

Related subtypes (4): cholangitis, extrahepatic cholestasis, obstructive jaundice, biliary atresia

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

7 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
188369	NM_138694.4(PKHD1):c.4870C>T (p.Arg1624Trp)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
577838	NM_138694.4(PKHD1):c.2702A>C (p.Asn901Thr)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
917964	NM_024926.4(IFT56):c.788A>G (p.Asn263Ser)	IFT56	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1162264	NM_138694.4(PKHD1):c.5879C>G (p.Thr1960Arg)	PKHD1	Likely pathogenic	criteria provided, single submitter
167489	NM_138694.4(PKHD1):c.3407A>G (p.Tyr1136Cys)	PKHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
96431	NM_138694.4(PKHD1):c.8345G>C (p.Gly2782Ala)	PKHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
96436	NM_138694.4(PKHD1):c.8606C>A (p.Thr2869Lys)	PKHD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · 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
PKD1	Strong	Autosomal dominant	Caroli disease	7
PRKD1	Strong	Autosomal dominant	Caroli disease	14
PKHD1	Supportive	Autosomal recessive	Caroli disease	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PKHD1	Orphanet:53035	Caroli disease
PKHD1	Orphanet:731	Autosomal recessive polycystic kidney disease
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PKHD1	HGNC:9016	ENSG00000170927	P08F94	Fibrocystin	gencc,clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	gencc
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	gencc
IFT56	HGNC:21882	ENSG00000105948	A0AVF1	Intraflagellar transport protein 56	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PKHD1	Fibrocystin	Promotes ciliogenesis in renal epithelial cells and therefore participates in the tubules formation and/ or ensures the maintenance of the architecture of the lumen of the kidney.
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…
IFT56	Intraflagellar transport protein 56	Component of the intraflagellar transport (IFT) complex B required for transport of proteins in the motile cilium.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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
Antibody/Immunoglobulin	2	14.6×	0.020
Kinase	1	6.9×	0.205
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PKHD1	Antibody/Immunoglobulin	yes		IPT_dom, PbH1, Pectin_lyase_fold/virulence
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE
IFT56	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC26

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
kidney epithelium	1
metanephros cortex	1
renal medulla	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
seminal vesicle	1
thoracic aorta	1
ventricular zone	1
bronchial epithelial cell	1
bronchus	1
epithelium of bronchus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PKHD1	51	tissue_specific	marker	kidney epithelium, renal medulla, metanephros cortex
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta
IFT56	188	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKD1	2,131
PKD1	1,370
PKHD1	1,211
IFT56	1,097

Intra-cohort edges

A	B	Sources
PKD1	PKHD1	string_interaction
PKD1	PRKD1	string_interaction
PKHD1	PRKD1	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PKD1	P98161	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IFT56	A0AVF1	91.82
PRKD1	Q15139	68.99
PKHD1	P08F94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
VxPx cargo-targeting to cilium	1	173.0×	0.027	PKD1
Sphingolipid de novo biosynthesis	1	95.2×	0.027	PRKD1
Intraflagellar transport	1	66.8×	0.027	IFT56
Sphingolipid metabolism	1	56.0×	0.027	PRKD1
Metabolism of lipids	1	10.5×	0.111	PRKD1
Metabolism	1	3.9×	0.237	PRKD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
branching morphogenesis of an epithelial tube	2	366.4×	0.001	PKHD1, PKD1
regulation of cell adhesion	2	153.2×	0.004	PKHD1, PKD1
metanephric distal tubule morphogenesis	1	4213.0×	0.007	PKD1
regulation of cholangiocyte proliferation	1	4213.0×	0.007	PKHD1
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	2106.5×	0.007	PRKD1
nitrogen cycle metabolic process	1	2106.5×	0.007	PKD1
mesonephric tubule development	1	2106.5×	0.007	PKD1
kidney development	2	70.2×	0.007	PKHD1, PKD1
lymph vessel morphogenesis	1	1404.3×	0.009	PKD1
metanephric proximal tubule development	1	1404.3×	0.009	PKD1
calcium-independent cell-matrix adhesion	1	1053.2×	0.009	PKD1
cellular response to norepinephrine stimulus	1	1053.2×	0.009	PRKD1
metanephric ascending thin limb development	1	1053.2×	0.009	PKD1
cilium assembly	2	36.8×	0.009	PKHD1, IFT56
mesonephric duct development	1	842.6×	0.010	PKD1
positive regulation of sarcomere organization	1	702.2×	0.010	PRKD1
regulation of establishment of planar polarity	1	702.2×	0.010	PKHD1
mitocytosis	1	702.2×	0.010	PKD1
intraciliary transport involved in cilium assembly	1	601.9×	0.010	IFT56
lung epithelium development	1	526.6×	0.010	PKD1
cellular response to hydroperoxide	1	526.6×	0.010	PRKD1
regulation of integrin-mediated signaling pathway	1	526.6×	0.010	PRKD1
response to fluid shear stress	1	468.1×	0.010	PKD1
homeostatic process	1	421.3×	0.010	PKHD1
genitalia development	1	421.3×	0.010	PKD1
establishment of centrosome localization	1	421.3×	0.010	PKHD1
metanephric collecting duct development	1	421.3×	0.010	PKD1
regulation of keratinocyte proliferation	1	383.0×	0.010	PRKD1
Golgi vesicle transport	1	383.0×	0.010	PRKD1
positive regulation of peptide hormone secretion	1	383.0×	0.010	PRKD1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKD1	26	4
PKHD1	0	0
PKD1	0	0
IFT56	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKD1	660	Binding:650, Functional:10
PKD1	27	Binding:27

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKD1	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

26 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)
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PKD1
D	Druggable family + AlphaFold only, no drug	1	PKHD1
E	Difficult family or no structure, no drug	1	IFT56

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)
PKD1	27	PRKD1
PKHD1	0	—
IFT56	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04007575	Not specified	COMPLETED	Study of New Imaging Criteria for the Diagnosis of Caroli’s Disease