Pontocerebellar hypoplasia type 4

Summary

Pontocerebellar hypoplasia type 4 (MONDO:0009166) is a disease caused by TSEN54 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TSEN54 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 44
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002365	Hypoplasia of the brainstem	Frequent (30-79%)
HP:0002804	Arthrogryposis multiplex congenita	Frequent (30-79%)
HP:0002871	Central apnea	Frequent (30-79%)
HP:0004887	Respiratory failure requiring assisted ventilation	Frequent (30-79%)
HP:0006955	Olivopontocerebellar hypoplasia	Frequent (30-79%)
HP:0011451	Congenital microcephaly	Frequent (30-79%)
HP:0000340	Sloping forehead	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0011800	Midface retrusion	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 4
Mondo ID	MONDO:0009166
MeSH	C536716
OMIM	225753
Orphanet	166063
DOID	DOID:0060273
ICD-11	447667859
SNOMED CT	718608006
UMLS	C1856974
MedGen	384027
GARD	0000343
Is cancer (heuristic)	no

Also known as: encephalopathy fatal infantile with olivopontocerebellar hypoplasia · fatal infantile encephalopathy with olivopontocerebellar hypoplasia · olivopontocerebellar hypoplasia · PCH4 · pontocerebellar hypoplasia, type 4

Data availability: 44 ClinVar variants · 2 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 4

Related subtypes (20): pontocerebellar hypoplasia type 3, pontocerebellar hypoplasia type 5, pontocerebellar hypoplasia type 6, pontocerebellar hypoplasia type 8, pontocerebellar hypoplasia type 7, 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

44 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 8 benign, 8 pathogenic/likely pathogenic, 8 pathogenic, 7 conflicting classifications of pathogenicity, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1454338	NM_207346.3(TSEN54):c.775C>T (p.Gln259Ter)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686281	NM_207346.3(TSEN54):c.221+3G>T	TSEN54	Pathogenic	criteria provided, single submitter
1705655	NM_207346.3(TSEN54):c.869_875dup (p.Lys293fs)	TSEN54	Pathogenic	criteria provided, single submitter
2120	NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser)	TSEN54	Pathogenic	criteria provided, multiple submitters, no conflicts
2122	NM_207346.3(TSEN54):c.736C>T (p.Gln246Ter)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2123	NM_207346.3(TSEN54):c.1027C>T (p.Gln343Ter)	TSEN54	Pathogenic	no assertion criteria provided
2395121	NM_207346.3(TSEN54):c.856_862dup (p.Val288fs)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2434304	NM_207346.3(TSEN54):c.789_798del (p.Leu264fs)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445207	NM_207346.3(TSEN54):c.953del (p.Pro318fs)	TSEN54	Pathogenic	criteria provided, multiple submitters, no conflicts
265282	NM_207346.3(TSEN54):c.670_671del (p.Lys224fs)	TSEN54	Pathogenic	criteria provided, multiple submitters, no conflicts
2745042	NM_207346.3(TSEN54):c.767del (p.Gly256fs)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2843217	NM_207346.3(TSEN54):c.846_856del (p.Ala284fs)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2850363	NM_207346.3(TSEN54):c.505C>T (p.Arg169Ter)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30751	NM_207346.3(TSEN54):c.1172_1185del (p.Gln391fs)	TSEN54	Pathogenic	criteria provided, single submitter
561138	NM_207346.3(TSEN54):c.940del (p.Leu314fs)	TSEN54	Pathogenic	criteria provided, multiple submitters, no conflicts
620188	NM_207346.3(TSEN54):c.1039A>T (p.Lys347Ter)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2121	TSEN54:c.[277T>C;919G>T]		Likely pathogenic	criteria provided, single submitter
3582828	NM_207346.3(TSEN54):c.80_102del (p.Arg27fs)	LOC112533671	Likely pathogenic	criteria provided, single submitter
1685466	NM_207346.3(TSEN54):c.249G>A (p.Arg83=)	TSEN54	Likely pathogenic	criteria provided, single submitter
4845811	NM_207346.3(TSEN54):c.743C>G (p.Ser248Ter)	TSEN54	Likely pathogenic	criteria provided, single submitter
96674	NM_207346.3(TSEN54):c.3_8dup (p.2_3EP[4])	LOC112533671	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1181537	NM_207346.3(TSEN54):c.766G>A (p.Gly256Ser)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1210718	NM_207346.3(TSEN54):c.1313G>A (p.Arg438Gln)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1219861	NM_207346.3(TSEN54):c.1136G>A (p.Arg379Gln)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
160124	NM_207346.3(TSEN54):c.1114G>A (p.Val372Met)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212455	NM_207346.3(TSEN54):c.83C>T (p.Ser28Leu)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
889594	NM_207346.3(TSEN54):c.369+5G>A	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1385645	NM_207346.3(TSEN54):c.946C>T (p.Arg316Cys)	TSEN54	Uncertain significance	criteria provided, multiple submitters, no conflicts
1491165	NM_207346.3(TSEN54):c.1186C>T (p.Arg396Trp)	TSEN54	Uncertain significance	criteria provided, multiple submitters, no conflicts
1492264	NM_207346.3(TSEN54):c.909C>G (p.Phe303Leu)	TSEN54	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
TSEN54	Strong	Autosomal recessive	pontocerebellar hypoplasia type 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSEN54	Orphanet:166063	Pontocerebellar hypoplasia type 4
TSEN54	Orphanet:2524	Pontocerebellar hypoplasia type 2

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
TSEN54	HGNC:27561	ENSG00000182173	Q7Z6J9	tRNA-splicing endonuclease subunit Sen54	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSEN54	tRNA-splicing endonuclease subunit Sen54	Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSEN54	Enzyme (other)	yes	4.6.1.16	tRNA_splic_suSen54_N, tRNA_splic_suSen54

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
cerebellar hemisphere	1
granulocyte	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSEN54	232	ubiquitous	marker	granulocyte, right uterine tube, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSEN54	1,085

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSEN54	Q7Z6J9	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
tRNA processing	1	356.9×	0.008	TSEN54
tRNA processing in the nucleus	1	196.9×	0.008	TSEN54
Metabolism of RNA	1	41.7×	0.024	TSEN54

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
tRNA-type intron splice site recognition and cleavage	1	5617.3×	5e-04	TSEN54
tRNA splicing, via endonucleolytic cleavage and ligation	1	1404.3×	0.001	TSEN54
mRNA processing	1	78.8×	0.013	TSEN54

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
TSEN54	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TSEN54	4.6.1.16	tRNA-intron lyase

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	TSEN54
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
TSEN54	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.