Cryptosporidiosis-chronic cholangitis-liver disease syndrome

Summary

Cryptosporidiosis-chronic cholangitis-liver disease syndrome (MONDO:0014082) is a disease caused by IL21R (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IL21R (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 368

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	cryptosporidiosis-chronic cholangitis-liver disease syndrome
Mondo ID	MONDO:0014082
OMIM	615207
Orphanet	357329
DOID	DOID:0111982
UMLS	C3554687
MedGen	767601
GARD	0017550
Is cancer (heuristic)	no

Also known as: cryptosporidiosis-chronic cholangitis-liver disease syndrome · IMD56

Data availability: 368 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 › cryptosporidiosis-chronic cholangitis-liver disease syndrome

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, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, 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

368 retrieved; paginated sample, class counts are floors:

172 likely benign, 160 uncertain significance, 11 conflicting classifications of pathogenicity, 9 benign, 6 pathogenic, 5 benign/likely benign, 5 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332701	NM_181078.3(IL21R):c.842dup (p.Tyr281Ter)	IL21R	Pathogenic	criteria provided, single submitter
2053574	NM_181078.3(IL21R):c.468T>A (p.Tyr156Ter)	IL21R	Pathogenic	criteria provided, single submitter
2105229	NM_181078.3(IL21R):c.27dup (p.Leu10fs)	IL21R	Pathogenic	criteria provided, single submitter
42199	NM_181078.3(IL21R):c.241_246del (p.Cys81_His82del)	IL21R	Pathogenic	no assertion criteria provided
42200	NM_181078.3(IL21R):c.602G>T (p.Arg201Leu)	IL21R	Pathogenic	no assertion criteria provided
4293560	NM_181078.3(IL21R):c.503_507+3del	IL21R	Pathogenic	criteria provided, single submitter
1687495	NM_181078.3(IL21R):c.946del (p.Val316fs)	IL21R	Likely pathogenic	criteria provided, single submitter
1900828	NM_181078.3(IL21R):c.686-2A>G	IL21R	Likely pathogenic	criteria provided, single submitter
3362656	NM_181078.3(IL21R):c.637del (p.Thr213fs)	IL21R	Likely pathogenic	criteria provided, single submitter
3693887	NM_181078.3(IL21R):c.507+1G>A	IL21R	Likely pathogenic	criteria provided, single submitter
973584	NM_181078.3(IL21R):c.352+1G>C	IL21R	Likely pathogenic	criteria provided, single submitter
1425251	NM_181078.3(IL21R):c.1073C>T (p.Ser358Leu)	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1598361	NM_181078.3(IL21R):c.1433C>T (p.Ala478Val)	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2201659	NM_181078.3(IL21R):c.1052T>C (p.Phe351Ser)	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
252799	NM_181078.3(IL21R):c.824G>A (p.Arg275Gln)	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
402977	NM_181078.3(IL21R):c.137C>T (p.Thr46Met)	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626116	NM_181078.3(IL21R):c.-17+563G>A	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
645716	NM_181078.3(IL21R):c.968G>A (p.Arg323Gln)	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
709593	NM_181078.3(IL21R):c.571C>T (p.Arg191Cys)	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
857678	NM_181078.3(IL21R):c.572G>A (p.Arg191His)	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
976232	NM_181078.3(IL21R):c.563del (p.Leu188fs)	IL21R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225037	NM_181078.3(IL21R):c.1033G>A (p.Gly345Ser)	LOC130058712	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001818	NM_181078.3(IL21R):c.149C>G (p.Thr50Ser)	IL21R	Uncertain significance	criteria provided, multiple submitters, no conflicts
1002481	NM_181078.3(IL21R):c.598G>A (p.Val200Met)	IL21R	Uncertain significance	criteria provided, single submitter
1005077	NM_181078.3(IL21R):c.508-7_508-6delinsAC	IL21R	Uncertain significance	criteria provided, single submitter
1010394	NM_181078.3(IL21R):c.20C>G (p.Ala7Gly)	IL21R	Uncertain significance	criteria provided, multiple submitters, no conflicts
1010685	NM_181078.3(IL21R):c.191C>T (p.Ser64Phe)	IL21R	Uncertain significance	criteria provided, single submitter
1018723	NM_181078.3(IL21R):c.1057C>T (p.Pro353Ser)	IL21R	Uncertain significance	criteria provided, single submitter
1020118	NM_181078.3(IL21R):c.977C>T (p.Ala326Val)	IL21R	Uncertain significance	criteria provided, single submitter
1025748	NM_181078.3(IL21R):c.1412G>C (p.Gly471Ala)	IL21R	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
IL21R	Strong	Autosomal recessive	cryptosporidiosis-chronic cholangitis-liver disease syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL21R	Orphanet:357329	Combined immunodeficiency due to IL21R deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL21R	HGNC:6006	ENSG00000103522	Q9HBE5	Interleukin-21 receptor	gencc,clinvar
IL21R-AS1	HGNC:27551	ENSG00000259954		IL21R antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL21R	Interleukin-21 receptor	This is a receptor for interleukin-21.

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL21R	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold
IL21R-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
lymph node	1
cerebellar hemisphere	1
colonic epithelium	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL21R	178	broad	marker	granulocyte, lymph node, blood
IL21R-AS1	130		yes	colonic epithelium, pituitary gland, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL21R	1,596
IL21R-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL21R	Q9HBE5	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Interleukin-21 signaling	1	1142.0×	9e-04	IL21R

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
natural killer cell activation	1	581.1×	0.003	IL21R
cytokine-mediated signaling pathway	1	130.6×	0.008	IL21R

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL21R	0	0
IL21R-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	IL21R
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	IL21R-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IL21R	0	—
IL21R-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.