Infantile-onset generalized dyskinesia with orofacial involvement

Summary

Infantile-onset generalized dyskinesia with orofacial involvement (MONDO:0044637) is a disease caused by PDE10A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PDE10A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 18
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0002310	Orofacial dyskinesia	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0011470	Nasogastric tube feeding in infancy	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0100248	Hemiballismus	Occasional (5-29%)
HP:0012444	Brain atrophy	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile-onset generalized dyskinesia with orofacial involvement
Mondo ID	MONDO:0044637
OMIM	616921
Orphanet	494526
UMLS	C5567464
MedGen	1798887
GARD	0017905
Is cancer (heuristic)	no

Also known as: dyskinesia, limb and orofacial, infantile-onset · infantile-onset orofacial-trunk-limbs dyskinesia · IOLOD

Data availability: 18 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia › isolated dystonia › focal, segmental or multifocal dystonia › infantile-onset generalized dyskinesia with orofacial involvement

Related subtypes (11): torsion dystonia 4, torsion dystonia 2, torsion dystonia 13, torsion dystonia 17, dystonia 23, dystonia 24, dystonia 25, dystonia 27, oromandibular dystonia, blepharospasm-oromandibular dystonia syndrome, adult-onset segmental dystonia

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

18 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 5 likely pathogenic, 2 benign, 2 pathogenic/likely pathogenic, 1 pathogenic, 1 likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
225633	NM_001385079.1(PDE10A):c.1118A>G (p.Tyr373Cys)	PDE10A	Pathogenic/Likely pathogenic	no assertion criteria provided
225634	NM_001385079.1(PDE10A):c.1144G>C (p.Ala382Pro)	PDE10A	Pathogenic	no assertion criteria provided
522607	NM_001385079.1(PDE10A):c.1799T>G (p.Phe600Cys)	PDE10A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708178	NM_001385079.1(PDE10A):c.2795T>G (p.Ile932Ser)	PDE10A	Likely pathogenic	no assertion criteria provided
1708179	NM_001385079.1(PDE10A):c.2133_2142del (p.Ser712fs)	PDE10A	Likely pathogenic	no assertion criteria provided
2031793	NM_001385079.1(PDE10A):c.1698C>G (p.Phe566Leu)	PDE10A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3780106	NM_001385079.1(PDE10A):c.2375dup (p.Asn792fs)	PDE10A	Likely pathogenic	criteria provided, single submitter
807460	NM_001385079.1(PDE10A):c.1450C>T (p.Arg484Trp)	PDE10A	Likely pathogenic	criteria provided, single submitter
804399	NM_001385079.1(PDE10A):c.1342C>T (p.Arg448Ter)	PDE10A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213809	NM_001385079.1(PDE10A):c.3128C>A (p.Ser1043Tyr)	PDE10A	Uncertain significance	criteria provided, single submitter
3376772	NM_001385079.1(PDE10A):c.1838C>G (p.Thr613Arg)	PDE10A	Uncertain significance	criteria provided, single submitter
3376773	NM_001385079.1(PDE10A):c.2113C>T (p.Arg705Trp)	PDE10A	Uncertain significance	criteria provided, single submitter
3775863	NM_001385079.1(PDE10A):c.3069_3070insTAT (p.Asp1023_Asn1024insTyr)	PDE10A	Uncertain significance	criteria provided, single submitter
3895500	NM_001385079.1(PDE10A):c.2455-2A>G	PDE10A	Uncertain significance	criteria provided, single submitter
4279792	NM_001385079.1(PDE10A):c.1136T>C (p.Ile379Thr)	PDE10A	Uncertain significance	criteria provided, single submitter
1164211	NM_001385079.1(PDE10A):c.1692G>A (p.Ala564=)	PDE10A	Benign	criteria provided, multiple submitters, no conflicts
1168261	NM_001385079.1(PDE10A):c.1890-19T>C	PDE10A	Benign	criteria provided, multiple submitters, no conflicts
753219	NM_001385079.1(PDE10A):c.1155C>T (p.Ala385=)	PDE10A	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
PDE10A	Strong	Autosomal recessive	dyskinesia, limb and orofacial, infantile-onset	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDE10A	Orphanet:494526	Infantile-onset generalized dyskinesia with orofacial involvement
PDE10A	Orphanet:494541	Childhood-onset benign chorea with striatal involvement

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
PDE10A	HGNC:8772	ENSG00000112541	Q9Y233	cAMP and cAMP-inhibited cGMP 3’,5’-cyclic phosphodiesterase 10A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDE10A	cAMP and cAMP-inhibited cGMP 3’,5’-cyclic phosphodiesterase 10A	Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDE10A	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, GAF, HD/PDEase_dom

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
adrenal tissue	1
cartilage tissue	1
left uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDE10A	219	broad	marker	adrenal tissue, left uterine tube, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDE10A	1,318

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE10A	Q9Y233	359

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
cGMP effects	1	713.8×	0.003	PDE10A
G alpha (s) signalling events	1	73.2×	0.014	PDE10A

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
cGMP catabolic process	1	3370.4×	7e-04	PDE10A
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	3370.4×	7e-04	PDE10A
negative regulation of receptor guanylyl cyclase signaling pathway	1	2808.7×	7e-04	PDE10A
cAMP catabolic process	1	1872.4×	8e-04	PDE10A
negative regulation of cAMP/PKA signal transduction	1	601.9×	0.002	PDE10A
signal transduction	1	16.1×	0.062	PDE10A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
PDE10A	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE10A	16	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARDENAFIL	4	PDE10A
SILDENAFIL	4	PDE10A
CINCHOPHEN	4	PDE10A
DIPYRIDAMOLE	4	PDE10A
PAPAVERINE	3	PDE10A
OXYCINCHOPHEN	2	PDE10A
ZAPRINAST	2	PDE10A
PF-06835919	2	PDE10A
MK-8189	2	PDE10A
MARDEPODECT	2	PDE10A
PAPAVERINE HYDROCHLORIDE	2	PDE10A
PF-04217903	1	PDE10A
JNJ-42396302	1	PDE10A
LENRISPODUN PHOSPHATE	1	PDE10A
PBF-999	1	PDE10A
AZD-7687	1	PDE10A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PDE10A	357	Binding:345, ADMET:9, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDE10A	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PDE10A	357

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

16 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)
VARDENAFIL	4	PDE10A
SILDENAFIL	4	PDE10A
CINCHOPHEN	4	PDE10A
DIPYRIDAMOLE	4	PDE10A
PAPAVERINE	3	PDE10A
OXYCINCHOPHEN	2	PDE10A
ZAPRINAST	2	PDE10A
PF-06835919	2	PDE10A
MK-8189	2	PDE10A
MARDEPODECT	2	PDE10A
PAPAVERINE HYDROCHLORIDE	2	PDE10A
PF-04217903	1	PDE10A
JNJ-42396302	1	PDE10A
LENRISPODUN PHOSPHATE	1	PDE10A
PBF-999	1	PDE10A
AZD-7687	1	PDE10A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PDE10A
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.