Cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome

Summary

Cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome (MONDO:0013208) is a disease caused by SLC30A10 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC30A10 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 63
• Phenotypes (HPO): 39

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	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:0000338	Hypomimic face	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001392	Abnormality of the liver	Frequent (30-79%)
HP:0001409	Portal hypertension	Frequent (30-79%)
HP:0001413	Micronodular cirrhosis	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001901	Polycythemia	Frequent (30-79%)
HP:0002040	Esophageal varix	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002345	Action tremor	Frequent (30-79%)
HP:0002453	Abnormal globus pallidus morphology	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0010927	Abnormal blood inorganic cation concentration	Frequent (30-79%)
HP:0012447	Abnormal myelination	Frequent (30-79%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Frequent (30-79%)
HP:0040135	Abnormal transferrin saturation	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)
HP:0001928	Abnormality of coagulation	Occasional (5-29%)
HP:0002078	Truncal ataxia	Occasional (5-29%)
HP:0002154	Hyperglycinemia	Occasional (5-29%)
HP:0002313	Spastic paraparesis	Occasional (5-29%)
HP:0002446	Astrocytosis	Occasional (5-29%)
HP:0004337	Abnormality of amino acid metabolism	Occasional (5-29%)
HP:0007010	Poor fine motor coordination	Occasional (5-29%)
HP:0008151	Prolonged prothrombin time	Occasional (5-29%)
HP:0012343	Decreased serum ferritin	Occasional (5-29%)
HP:0025196	Increased total iron binding capacity	Occasional (5-29%)
HP:0025321	Copper accumulation in liver	Occasional (5-29%)
HP:0100513	Low levels of vitamin E	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome
Mondo ID	MONDO:0013208
MeSH	C548016
OMIM	613280
Orphanet	309854
DOID	DOID:0080536
SNOMED CT	702377007
UMLS	C2750442
MedGen	412958
GARD	0010706
Is cancer (heuristic)	no

Also known as: cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome · HMDPC · HMNDYT1 · hypermanganesemia with dystonia polycythemia and cirrhosis · hypermanganesemia with dystonia, polycythemia, and cirrhosis

Data availability: 63 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 › inborn errors of metabolism › hypermanganesemia with dystonia › cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome

Related subtypes (1): hypermanganesemia with dystonia 2

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

63 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 8 conflicting classifications of pathogenicity, 7 not provided, 6 pathogenic, 4 likely pathogenic, 4 benign, 4 benign/likely benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
38295	nsv1067840	LOC129388752	Pathogenic	no assertion criteria provided
30885	NM_018713.3(SLC30A10):c.314_322del (p.Ala105_Pro107del)	SLC30A10	Pathogenic	no assertion criteria provided
30886	NM_018713.3(SLC30A10):c.266T>C (p.Leu89Pro)	SLC30A10	Pathogenic	no assertion criteria provided
30887	NM_018713.3(SLC30A10):c.585del (p.Thr196fs)	SLC30A10	Pathogenic	criteria provided, single submitter
30888	NM_018713.3(SLC30A10):c.507del (p.Pro170fs)	SLC30A10	Pathogenic	no assertion criteria provided
30889	NM_018713.3(SLC30A10):c.1235del (p.Gln412fs)	SLC30A10	Pathogenic	no assertion criteria provided
2682640	NM_018713.3(SLC30A10):c.392T>G (p.Leu131Arg)	SLC30A10	Likely pathogenic	no assertion criteria provided
3362498	NM_018713.3(SLC30A10):c.134dup (p.Ser46fs)	SLC30A10	Likely pathogenic	criteria provided, single submitter
38410	NM_018713.3(SLC30A10):c.922C>T (p.Gln308Ter)	SLC30A10	Likely pathogenic	criteria provided, single submitter
3895514	NM_018713.3(SLC30A10):c.511C>T (p.Gln171Ter)	SLC30A10	Likely pathogenic	criteria provided, single submitter
295582	NM_018713.3(SLC30A10):c.1449G>A (p.Thr483=)	SLC30A10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295585	NM_018713.3(SLC30A10):c.1118C>A (p.Ala373Glu)	SLC30A10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295588	NM_018713.3(SLC30A10):c.719-6T>C	SLC30A10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295593	NM_018713.3(SLC30A10):c.284C>T (p.Thr95Ile)	SLC30A10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
375609	NM_018713.3(SLC30A10):c.1006C>T (p.His336Tyr)	SLC30A10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875813	NM_018713.3(SLC30A10):c.1248C>T (p.Pro416=)	SLC30A10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875814	NM_018713.3(SLC30A10):c.789T>C (p.Tyr263=)	SLC30A10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876801	NM_018713.3(SLC30A10):c.624G>A (p.Val208=)	SLC30A10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2442166	NM_001376929.1(SLC30A10):c.254C>T (p.Thr85Ile)	SLC30A10	Uncertain significance	criteria provided, single submitter
295579	NM_018713.3(SLC30A10):c.*397C>T	SLC30A10	Uncertain significance	criteria provided, single submitter
295581	NM_018713.3(SLC30A10):c.*239A>G	SLC30A10	Uncertain significance	criteria provided, single submitter
295584	NM_018713.3(SLC30A10):c.1249C>G (p.Pro417Ala)	SLC30A10	Uncertain significance	criteria provided, single submitter
295586	NM_018713.3(SLC30A10):c.1068C>T (p.Asp356=)	SLC30A10	Uncertain significance	criteria provided, single submitter
295587	NM_018713.3(SLC30A10):c.907G>A (p.Ala303Thr)	SLC30A10	Uncertain significance	criteria provided, multiple submitters, no conflicts
295589	NM_018713.3(SLC30A10):c.676A>G (p.Met226Val)	SLC30A10	Uncertain significance	criteria provided, multiple submitters, no conflicts
295592	NM_018713.3(SLC30A10):c.440G>C (p.Gly147Ala)	SLC30A10	Uncertain significance	criteria provided, single submitter
295594	NM_018713.3(SLC30A10):c.76C>G (p.Leu26Val)	SLC30A10	Uncertain significance	criteria provided, single submitter
295595	NM_018713.3(SLC30A10):c.-19G>A	SLC30A10	Uncertain significance	criteria provided, single submitter
295596	NM_018713.3(SLC30A10):c.-20C>A	SLC30A10	Uncertain significance	criteria provided, single submitter
295598	NM_018713.3(SLC30A10):c.-68C>T	SLC30A10	Uncertain significance	criteria provided, single submitter

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
SLC30A10	Strong	Autosomal recessive	cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC30A10	Orphanet:309854	Cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC30A10	HGNC:25355	ENSG00000196660	Q6XR72	Calcium/manganese antiporter SLC30A10	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC30A10	Calcium/manganese antiporter SLC30A10	Calcium:manganese antiporter of the plasma membrane mediating the efflux of intracellular manganese coupled to an active extracellular calcium exchange.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC30A10	Other/Unknown	no		Cation_efflux, Cation_efflux_TMD_sf, Cation_efflux_CTD

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC30A10	111	broad	marker	jejunal mucosa, right lobe of liver, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC30A10	1,471

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC30A10	Q6XR72	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
Metal ion SLC transporters	1	601.0×	0.002	SLC30A10

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
manganese ion export across plasma membrane	1	16852.0×	6e-04	SLC30A10
detoxification of zinc ion	1	8426.0×	6e-04	SLC30A10
intracellular manganese ion homeostasis	1	3370.4×	7e-04	SLC30A10
zinc ion import into organelle	1	3370.4×	7e-04	SLC30A10
manganese ion transport	1	2106.5×	9e-04	SLC30A10
cellular response to angiotensin	1	936.2×	0.002	SLC30A10
zinc ion transmembrane transport	1	702.2×	0.002	SLC30A10
intracellular zinc ion homeostasis	1	481.5×	0.003	SLC30A10
epidermal growth factor receptor signaling pathway	1	247.8×	0.004	SLC30A10
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.012	SLC30A10

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
SLC30A10	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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC30A10

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC30A10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.