Pontocerebellar hypoplasia type 7

Summary

Pontocerebellar hypoplasia type 7 (MONDO:0013993) is a disease caused by TOE1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TOE1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 37
• Phenotypes (HPO): 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000062	Ambiguous genitalia	Frequent (30-79%)
HP:0000215	Thick upper lip vermilion	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0002060	Abnormal cerebral morphology	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002365	Hypoplasia of the brainstem	Frequent (30-79%)
HP:0002380	Fasciculations	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0006955	Olivopontocerebellar hypoplasia	Frequent (30-79%)
HP:0030197	Fatigable weakness of skeletal muscles	Frequent (30-79%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000133	Gonadal dysgenesis	Occasional (5-29%)
HP:0000151	Aplasia of the uterus	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0004305	Involuntary movements	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0008665	Clitoral hypertrophy	Occasional (5-29%)
HP:0012856	Abnormal scrotal rugation	Occasional (5-29%)
HP:0030260	Microphallus	Occasional (5-29%)
HP:0030261	Absent penis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 7
Mondo ID	MONDO:0013993
OMIM	614969
Orphanet	284339
DOID	DOID:0060276
SNOMED CT	718605009
UMLS	C3554226
MedGen	767140
GARD	0017315
Is cancer (heuristic)	no

Also known as: non-syndromic pontocerebellar hypoplasia caused by mutation in TOE1 · PCH7 · pontocerebellar hypoplasia, type 7 · pontocerebellar hypoplasia-46,XY disorder of sex development syndrome · TOE1 non-syndromic pontocerebellar hypoplasia

Data availability: 37 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › pontocerebellar hypoplasia › pontocerebellar hypoplasia type 7

Related subtypes (20): pontocerebellar hypoplasia type 4, pontocerebellar hypoplasia type 3, pontocerebellar hypoplasia type 5, pontocerebellar hypoplasia type 6, pontocerebellar hypoplasia type 8, pontocerebellar hypoplasia type 10, pontocerebellar hypoplasia type 9, pontocerebellar hypoplasia type 2E, pontocerebellar hypoplasia type 1, pontocerebellar hypoplasia type 2, pontocerebellar hypoplasia, type 14, pontocerebellar hypoplasia, type 15, pontocerebellar hypoplasia, type 1E, pontocerebellar hypoplasia, type 1F, pontocerebellar hypoplasia, type 16, pontocerebellar hypoplasia, IIA 17, pontocerebellar hypoplasia, type 12, pontocerebellar hypoplasia, type 13, pontocerebellar hypoplasia, type 11, pontocerebellar hypoplasia, type 1D

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

37 retrieved; paginated sample, class counts are floors:

14 likely pathogenic, 13 uncertain significance, 3 conflicting classifications of pathogenicity, 3 pathogenic, 2 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
417746	NM_025077.4(TOE1):c.658G>A (p.Glu220Lys)	TOE1	Pathogenic/Likely pathogenic	no assertion criteria provided
417748	NM_025077.4(TOE1):c.307G>A (p.Ala103Thr)	TOE1	Pathogenic/Likely pathogenic	no assertion criteria provided
417749	NM_025077.4(TOE1):c.518T>G (p.Val173Gly)	TOE1	Pathogenic	criteria provided, single submitter
417751	NM_025077.4(TOE1):c.957C>A (p.His319Gln)	TOE1	Pathogenic	no assertion criteria provided
524117	NM_025077.4(TOE1):c.940_941del (p.Gln314fs)	TOE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1275738	NM_025077.4(TOE1):c.551G>T (p.Arg184Leu)	TOE1	Likely pathogenic	criteria provided, single submitter
1279928	NM_025077.4(TOE1):c.237-2A>G	TOE1	Likely pathogenic	criteria provided, single submitter
1325214	NM_025077.4(TOE1):c.1018C>T (p.Arg340Ter)	TOE1	Likely pathogenic	criteria provided, single submitter
1676460	NM_025077.4(TOE1):c.544C>T (p.Arg182Ter)	TOE1	Likely pathogenic	criteria provided, single submitter
1687385	NM_025077.4(TOE1):c.1062del (p.Thr355fs)	TOE1	Likely pathogenic	criteria provided, single submitter
4813066	NM_025077.4(TOE1):c.764del (p.Asn255fs)	TOE1	Likely pathogenic	criteria provided, single submitter
690333	NM_025077.4(TOE1):c.937C>G (p.Pro313Ala)	TOE1	Likely pathogenic	no assertion criteria provided
690334	NM_025077.4(TOE1):c.957C>T (p.His319=)	TOE1	Likely pathogenic	no assertion criteria provided
690335	NM_025077.4(TOE1):c.955C>T (p.His319Tyr)	TOE1	Likely pathogenic	no assertion criteria provided
690336	NM_025077.4(TOE1):c.219G>C (p.Arg73Ser)	TOE1	Likely pathogenic	no assertion criteria provided
690337	NM_025077.4(TOE1):c.716T>C (p.Phe239Ser)	TOE1	Likely pathogenic	no assertion criteria provided
690339	NM_025077.4(TOE1):c.693T>A (p.Tyr231Ter)	TOE1	Likely pathogenic	no assertion criteria provided
690340	NM_025077.4(TOE1):c.1487C>T (p.Ser496Phe)	TOE1	Likely pathogenic	no assertion criteria provided
930764	NM_025077.4(TOE1):c.913-2A>G	TOE1	Likely pathogenic	criteria provided, single submitter
138310	NM_025077.4(TOE1):c.-45G>A	MUTYH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036796	NM_025077.4(TOE1):c.745C>T (p.Arg249Trp)	TOE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417747	NM_025077.4(TOE1):c.443T>A (p.Phe148Tyr)	TOE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2437176	NM_025077.4(TOE1):c.20A>G (p.Asp7Gly)	MUTYH	Uncertain significance	criteria provided, single submitter
1028867	NM_025077.4(TOE1):c.1159G>A (p.Asp387Asn)	TOE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028868	NM_025077.4(TOE1):c.1439G>A (p.Gly480Asp)	TOE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1474361	NM_025077.4(TOE1):c.940C>G (p.Gln314Glu)	TOE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1683722	NM_025077.4(TOE1):c.911C>T (p.Ser304Leu)	TOE1	Uncertain significance	criteria provided, single submitter
1687583	NM_025077.4(TOE1):c.1469G>A (p.Ser490Asn)	TOE1	Uncertain significance	criteria provided, single submitter
2053005	NM_025077.4(TOE1):c.242T>C (p.Ile81Thr)	TOE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2504593	NM_025077.4(TOE1):c.1476C>G (p.Phe492Leu)	TOE1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 5 · 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
MINPP1	Strong	Autosomal recessive	pontocerebellar hypoplasia, type 16	4
TOE1	Strong	Autosomal recessive	pontocerebellar hypoplasia type 7	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TOE1	Orphanet:284339	Pontocerebellar hypoplasia type 7
MINPP1	Orphanet:284339	Pontocerebellar hypoplasia type 7
MINPP1	Orphanet:319487	Familial papillary or follicular thyroid carcinoma
MUTYH	Orphanet:247798	MUTYH-related polyposis
MUTYH	Orphanet:440437	Familial colorectal cancer Type X

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
TOE1	HGNC:15954	ENSG00000132773	Q96GM8	Target of EGR1 protein 1	gencc,clinvar
MINPP1	HGNC:7102	ENSG00000107789	Q9UNW1	Multiple inositol polyphosphate phosphatase 1	gencc
MUTYH	HGNC:7527	ENSG00000132781	Q9UIF7	Adenine DNA glycosylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TOE1	Target of EGR1 protein 1	Inhibits cell growth rate and cell cycle.
MINPP1	Multiple inositol polyphosphate phosphatase 1	Multiple inositol polyphosphate phosphatase that hydrolyzes 1D-myo-inositol 1,3,4,5,6-pentakisphosphate (InsP5[2OH]) and 1D-myo-inositol hexakisphosphate (InsP6) to a range of less phosphorylated inositol phosphates.
MUTYH	Adenine DNA glycosylase	Involved in oxidative DNA damage repair.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TOE1	Transcription factor	no		Znf_CCCH, RNase_CAF1, RNaseH-like_sf
MINPP1	Enzyme (other)	yes	3.1.3.62	His_Pase_clade-2, Histidine_acid_Pase_euk, His_PPase_superfam
MUTYH	Other/Unknown	no		NUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain

Expression context

Cohort genes with no expression data: 0.

2 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
olfactory bulb	1
primordial germ cell in gonad	1
type B pancreatic cell	1
adrenal tissue	1
tibia	1
trabecular bone tissue	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TOE1	268	ubiquitous	yes	type B pancreatic cell, olfactory bulb, primordial germ cell in gonad
MINPP1	275	ubiquitous	marker	trabecular bone tissue, tibia, adrenal tissue
MUTYH	134	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TOE1	1,867
MUTYH	1,815
MINPP1	821

Intra-cohort edges

A	B	Sources
MUTYH	TOE1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MUTYH	Q9UIF7	3
TOE1	Q96GM8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MINPP1	Q9UNW1	90.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of IPs in the ER lumen	1	5710.0×	5e-04	MINPP1
Defective MUTYH substrate binding	1	5710.0×	5e-04	MUTYH
Defective MUTYH substrate processing	1	5710.0×	5e-04	MUTYH
Displacement of DNA glycosylase by APEX1	1	519.1×	0.004	MUTYH
Inositol phosphate metabolism	1	237.9×	0.007	MINPP1
Recognition and association of DNA glycosylase with site containing an affected purine	1	102.0×	0.011	MUTYH
Cleavage of the damaged purine	1	102.0×	0.011	MUTYH
Metabolism	1	5.8×	0.165	MINPP1

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
depurination	1	1404.3×	0.006	MUTYH
snRNA 3’-end processing	1	432.1×	0.006	TOE1
intracellular monoatomic cation homeostasis	1	374.5×	0.006	MINPP1
inositol phosphate metabolic process	1	330.4×	0.006	MINPP1
negative regulation of necroptotic process	1	330.4×	0.006	MUTYH
mismatch repair	1	216.1×	0.008	MUTYH
base-excision repair	1	156.0×	0.009	MUTYH
bone mineralization	1	90.6×	0.014	MINPP1
ossification	1	75.9×	0.015	MINPP1
DNA repair	1	21.3×	0.046	MUTYH

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TOE1	1	2
MINPP1	0	0
MUTYH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	TOE1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TOE1	6	Binding:6
MUTYH	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MINPP1	3.1.3.62	multiple inositol-polyphosphate phosphatase

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

1 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)
MOLIBRESIB	2	TOE1

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	1	TOE1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	MINPP1
E	Difficult family or no structure, no drug	1	MUTYH

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)
MINPP1	0	—
MUTYH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.