Hepatic veno-occlusive disease-immunodeficiency syndrome

Summary

Hepatic veno-occlusive disease-immunodeficiency syndrome (MONDO:0009338) is a disease caused by SP110 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SP110 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 509
• Phenotypes (HPO): 39

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		28	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0011117	Abnormal circulating interleukin concentration	Very frequent (80-99%)
HP:0003139	Panhypogammaglobulinemia	Very frequent (80-99%)
HP:0030355	Abnormal serum interferon-gamma level	Very frequent (80-99%)
HP:0040088	Abnormal lymphocyte count	Very frequent (80-99%)
HP:0005403	Decreased total T cell count	Frequent (30-79%)
HP:0012735	Cough	Frequent (30-79%)
HP:0030374	Decreased proportion of memory B cells	Frequent (30-79%)
HP:0031123	Recurrent gastroenteritis	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002743	Recurrent enteroviral infections	Frequent (30-79%)
HP:0002849	Absence of lymph node germinal center	Frequent (30-79%)
HP:0004429	Recurrent viral infections	Frequent (30-79%)
HP:0000016	Urinary retention	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001409	Portal hypertension	Occasional (5-29%)
HP:0001541	Ascites	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002100	Recurrent aspiration pneumonia	Occasional (5-29%)
HP:0002206	Pulmonary fibrosis	Occasional (5-29%)
HP:0002385	Paraparesis	Occasional (5-29%)
HP:0002415	Leukodystrophy	Occasional (5-29%)
HP:0002722	Recurrent abscess formation	Occasional (5-29%)
HP:0002728	Chronic mucocutaneous candidiasis	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0010550	Paraplegia	Occasional (5-29%)
HP:0031218	Inappropriate antidiuretic hormone secretion	Occasional (5-29%)
HP:0040223	Pulmonary hemorrhage	Occasional (5-29%)
HP:0100626	Chronic hepatic failure	Occasional (5-29%)
HP:0410018	Recurrent ear infections	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0040089	Abnormal natural killer cell count	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hepatic veno-occlusive disease-immunodeficiency syndrome
Mondo ID	MONDO:0009338
MeSH	C537257
OMIM	235550
Orphanet	79124
DOID	DOID:0112254
ICD-11	712514250
SNOMED CT	724361001
UMLS	C1856128
MedGen	344659
GARD	0010083
Is cancer (heuristic)	no

Also known as: familial veno-occlusive disease with immunodeficiency · hepatic veno-occlusive disease with immunodeficiency · hepatic venoocclusive disease with immunodeficiency · veno-occlusive disease and immunodeficiency syndrome · VODI · VODI syndrome

Data availability: 509 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › hepatic veno-occlusive disease-immunodeficiency syndrome

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

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

509 retrieved; paginated sample, class counts are floors:

208 uncertain significance, 192 likely benign, 26 pathogenic, 26 benign, 23 conflicting classifications of pathogenicity, 13 likely pathogenic, 9 pathogenic/likely pathogenic, 9 benign/likely benign, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028771	NM_080424.4(SP110):c.1891C>T (p.Arg631Ter)	SP110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069349	NC_000002.11:g.(?231033820)(231086456_?)del	SP110	Pathogenic	criteria provided, single submitter
1069882	NM_080424.4(SP110):c.1428_1429del (p.Tyr476_Lys477delinsTer)	SP110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071115	NM_080424.4(SP110):c.1116_1119del (p.Arg373fs)	SP110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1218517	NM_080424.4(SP110):c.1660C>T (p.Arg554Ter)	SP110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1390383	NM_080424.4(SP110):c.436C>T (p.Gln146Ter)	SP110	Pathogenic	criteria provided, single submitter
1424039	NM_080424.4(SP110):c.1362dup (p.Asp455Ter)	SP110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451450	NM_080424.4(SP110):c.1342C>T (p.Arg448Ter)	SP110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451662	NM_080424.4(SP110):c.1933del (p.Leu645fs)	SP110	Pathogenic	criteria provided, single submitter
1458064	NM_080424.4(SP110):c.1775_1778del (p.Val591_Ser592insTer)	SP110	Pathogenic	criteria provided, single submitter
1460016	NC_000002.11:g.(?231042234)(231042416_?)del	SP110	Pathogenic	criteria provided, single submitter
1912459	NM_080424.4(SP110):c.886del (p.Ser296fs)	SP110	Pathogenic	criteria provided, single submitter
2024159	NM_080424.4(SP110):c.463A>T (p.Arg155Ter)	SP110	Pathogenic	criteria provided, single submitter
2155154	NM_080424.4(SP110):c.1067C>A (p.Ser356Ter)	SP110	Pathogenic	criteria provided, single submitter
2416113	NM_080424.4(SP110):c.1631dup (p.Gln545fs)	SP110	Pathogenic	criteria provided, single submitter
2425135	NC_000002.11:g.(?231033840)(231081642_?)del	SP110	Pathogenic	criteria provided, single submitter
2897348	NM_080424.4(SP110):c.943del (p.Val315fs)	SP110	Pathogenic	criteria provided, single submitter
3247280	NC_000002.11:g.(?231065581)(231081642_?)del	SP110	Pathogenic	criteria provided, single submitter
4714257	NM_080424.4(SP110):c.1493_1494insCAAC (p.Pro499fs)	SP110	Pathogenic	criteria provided, single submitter
4721716	NM_080424.4(SP110):c.1359_1360del (p.Lys453_Ser454insTer)	SP110	Pathogenic	criteria provided, single submitter
5538	NM_080424.4(SP110):c.40del (p.Gln14fs)	SP110	Pathogenic	no assertion criteria provided
574936	NM_080424.4(SP110):c.1395dup (p.Val466fs)	SP110	Pathogenic	criteria provided, single submitter
817546	NM_080424.4(SP110):c.1261C>T (p.Arg421Ter)	SP110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
832842	NC_000002.12:g.(?230176645)(230177700_?)del	SP110	Pathogenic	criteria provided, single submitter
840660	NM_080424.4(SP110):c.1030C>T (p.Arg344Ter)	SP110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
971546	NM_080424.4(SP110):c.1691del (p.Pro564fs)	SP110	Pathogenic	criteria provided, single submitter
1323637	NM_080424.4(SP110):c.1114C>T (p.Arg372Ter)	SP140	Pathogenic	criteria provided, single submitter
1392592	NM_080424.4(SP110):c.699del (p.Asp234fs)	SP140	Pathogenic	criteria provided, single submitter
2816180	NM_080424.4(SP110):c.299del (p.Tyr100fs)	SP140	Pathogenic	criteria provided, single submitter
2819031	NM_080424.4(SP110):c.80dup (p.His28fs)	SP140	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 7 · 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
PMP22	Strong	Autosomal recessive	hepatic veno-occlusive disease-immunodeficiency syndrome	21
SP110	Strong	Autosomal recessive	hepatic veno-occlusive disease-immunodeficiency syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SP110	Orphanet:79124	Hepatic veno-occlusive disease-immunodeficiency syndrome
PMP22	Orphanet:101081	Charcot-Marie-Tooth disease type 1A
PMP22	Orphanet:3115	Roussy-Lévy syndrome
PMP22	Orphanet:640	Hereditary neuropathy with liability to pressure palsies
PMP22	Orphanet:64748	Dejerine-Sottas syndrome
PMP22	Orphanet:90658	Charcot-Marie-Tooth disease type 1E
PMP22	Orphanet:98916	Acute inflammatory demyelinating polyradiculoneuropathy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SP110	HGNC:5401	ENSG00000135899	Q9HB58	Sp110 nuclear body protein	gencc,clinvar
PMP22	HGNC:9118	ENSG00000109099	Q01453	Peripheral myelin protein 22	gencc,clinvar
SP140	HGNC:17133	ENSG00000079263	Q13342	Nuclear body protein SP140	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SP110	Sp110 nuclear body protein	Transcription factor.
PMP22	Peripheral myelin protein 22	Might be involved in growth regulation, and in myelinization in the peripheral nervous system.
SP140	Nuclear body protein SP140	Component of the nuclear body, also known as nuclear domain 10, PML oncogenic domain, and KR body.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Transcription factor	2	5.5×	0.081
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SP110	Transcription factor	no		SAND_dom, Bromodomain, Znf_PHD
PMP22	Other/Unknown	no		PMP22, PMP22/EMP/MP20/Claudin, PMP22_EMP_MP20
SP140	Transcription factor	no		SAND_dom, Bromodomain, Znf_PHD

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
dorsal root ganglion	1
olfactory bulb	1
trigeminal ganglion	1
granulocyte	1
lymph node	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SP110	288	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
PMP22	294	ubiquitous	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion
SP140	178	broad	marker	lymph node, granulocyte, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SP110	1,253
SP140	1,219
PMP22	647

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SP140	Q13342	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PMP22	Q01453	89.87
SP110	Q9HB58	58.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 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
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	368.4×	0.003	PMP22

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
myelin assembly	1	624.1×	0.010	PMP22
bleb assembly	1	510.7×	0.010	PMP22
peripheral nervous system development	1	193.7×	0.017	PMP22
negative regulation of neuron projection development	1	79.1×	0.028	PMP22
defense response	1	72.0×	0.028	SP140
regulation of transcription by RNA polymerase II	2	7.8×	0.035	SP110, SP140
chemical synaptic transmission	1	25.8×	0.055	PMP22
negative regulation of cell population proliferation	1	14.0×	0.087	PMP22
cell differentiation	1	9.7×	0.101	PMP22
apoptotic process	1	9.6×	0.101	PMP22

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
PMP22	PROGESTERONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PMP22	213	4
SP110	0	0
SP140	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	PMP22
CLOTRIMAZOLE	4	PMP22
OXAPROZIN	4	PMP22
SALMETEROL XINAFOATE	4	PMP22
AMIODARONE HYDROCHLORIDE	4	PMP22
TRIHEXYPHENIDYL HYDROCHLORIDE	4	PMP22
AMOXAPINE	4	PMP22
RALOXIFENE HYDROCHLORIDE	4	PMP22
IDARUBICIN	4	PMP22
OXYBUTYNIN CHLORIDE	4	PMP22
PINACIDIL ANHYDROUS	4	PMP22
NICARDIPINE HYDROCHLORIDE	4	PMP22
PILOCARPINE HYDROCHLORIDE	4	PMP22
PROTRIPTYLINE HYDROCHLORIDE	4	PMP22
BENZTROPINE MESYLATE	4	PMP22
BUSPIRONE HYDROCHLORIDE	4	PMP22
DOBUTAMINE HYDROCHLORIDE	4	PMP22
PROMAZINE HYDROCHLORIDE	4	PMP22
DICYCLOMINE HYDROCHLORIDE	4	PMP22
GUANFACINE HYDROCHLORIDE	4	PMP22
HYDROCORTISONE SODIUM SUCCINATE	4	PMP22
BROMOCRIPTINE MESYLATE	4	PMP22
DIHYDROERGOTAMINE MESYLATE	4	PMP22
DOXAZOSIN MESYLATE	4	PMP22
CYCLOBENZAPRINE HYDROCHLORIDE	4	PMP22
DEXBROMPHENIRAMINE MALEATE	4	PMP22
CLOMIPRAMINE HYDROCHLORIDE	4	PMP22
CHLORMEZANONE	4	PMP22
PROMETHAZINE HYDROCHLORIDE	4	PMP22
CITALOPRAM HYDROBROMIDE	4	PMP22

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SP140	8	Binding:8
SP110	2	Binding:2
PMP22	1	Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
PROGESTERONE	4	PMP22
CLOTRIMAZOLE	4	PMP22
OXAPROZIN	4	PMP22
SALMETEROL XINAFOATE	4	PMP22
AMIODARONE HYDROCHLORIDE	4	PMP22
TRIHEXYPHENIDYL HYDROCHLORIDE	4	PMP22
AMOXAPINE	4	PMP22
RALOXIFENE HYDROCHLORIDE	4	PMP22
IDARUBICIN	4	PMP22
OXYBUTYNIN CHLORIDE	4	PMP22
PINACIDIL ANHYDROUS	4	PMP22
NICARDIPINE HYDROCHLORIDE	4	PMP22
PILOCARPINE HYDROCHLORIDE	4	PMP22
PROTRIPTYLINE HYDROCHLORIDE	4	PMP22
BENZTROPINE MESYLATE	4	PMP22
BUSPIRONE HYDROCHLORIDE	4	PMP22
DOBUTAMINE HYDROCHLORIDE	4	PMP22
PROMAZINE HYDROCHLORIDE	4	PMP22
DICYCLOMINE HYDROCHLORIDE	4	PMP22
GUANFACINE HYDROCHLORIDE	4	PMP22
HYDROCORTISONE SODIUM SUCCINATE	4	PMP22
BROMOCRIPTINE MESYLATE	4	PMP22
DIHYDROERGOTAMINE MESYLATE	4	PMP22
DOXAZOSIN MESYLATE	4	PMP22
CYCLOBENZAPRINE HYDROCHLORIDE	4	PMP22
DEXBROMPHENIRAMINE MALEATE	4	PMP22
CLOMIPRAMINE HYDROCHLORIDE	4	PMP22
CHLORMEZANONE	4	PMP22
PROMETHAZINE HYDROCHLORIDE	4	PMP22
CITALOPRAM HYDROBROMIDE	4	PMP22

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PMP22
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	2	SP110, SP140

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)
SP110	2	—
SP140	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.