Pontocerebellar hypoplasia type 2

Summary

Pontocerebellar hypoplasia type 2 (MONDO:0016759) is a disease (an umbrella term covering 5 Mondo subtypes) with 5 cohort genes. The dominant Reactome pathway is tRNA processing (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 1
• Phenotypes (HPO): 40

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		81	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001266	Choreoathetosis	Very frequent (80-99%)
HP:0001320	Cerebellar vermis hypoplasia	Very frequent (80-99%)
HP:0001321	Cerebellar hypoplasia	Very frequent (80-99%)
HP:0002123	Generalized myoclonic seizure	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0006850	Hypoplasia of the ventral pons	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0031162	Impaired oropharyngeal swallow response	Very frequent (80-99%)
HP:0000253	Progressive microcephaly	Frequent (30-79%)
HP:0000340	Sloping forehead	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0002104	Apnea	Frequent (30-79%)
HP:0002268	Paroxysmal dystonia	Frequent (30-79%)
HP:0002365	Hypoplasia of the brainstem	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0012469	Infantile spasms	Frequent (30-79%)
HP:0200136	Oral-pharyngeal dysphagia	Frequent (30-79%)
HP:0008936	Axial hypotonia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002536	Abnormal cortical gyration	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0003558	Viral infection-induced rhabdomyolysis	Occasional (5-29%)
HP:0006895	Lower limb hypertonia	Occasional (5-29%)
HP:0006989	Dysplastic corpus callosum	Occasional (5-29%)
HP:0007598	Bilateral single transverse palmar creases	Occasional (5-29%)
HP:0011171	Simple febrile seizures	Occasional (5-29%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0012765	Widened cerebellar subarachnoid space	Occasional (5-29%)
HP:0025190	Bilateral tonic-clonic seizure with generalized onset	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)
HP:0200049	Upper limb hypertonia	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Excluded (0%)
HP:0002350	Cerebellar cyst	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 2
Mondo ID	MONDO:0016759
MeSH	C548070
Orphanet	2524
DOID	DOID:0112328
ICD-11	1158649247
NCIT	C124057
SNOMED CT	715463008
UMLS	C2932714
MedGen	420956
GARD	0010705
Is cancer (heuristic)	no

Also known as: PCH2 · progressive microcephaly from birth extrapyramidal dyskinesia chorea epilepsy

Data availability: 1 ClinVar variant · 5 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › spinal muscular atrophy › bulbospinal muscular atrophy › pontocerebellar hypoplasia type 2

Related subtypes (2): spinal atrophy-ophthalmoplegia-pyramidal syndrome, pontocerebellar hypoplasia type 1

Subtypes (5): pontocerebellar hypoplasia type 2A, pontocerebellar hypoplasia type 2B, pontocerebellar hypoplasia type 2C, pontocerebellar hypoplasia type 2D, pontocerebellar hypoplasia, type 2F

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2120	NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser)	TSEN54	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · 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
SEPSECS	Definitive	Autosomal recessive	pontocerebellar hypoplasia type 2D	7
TSEN15	Strong	Autosomal recessive	pontocerebellar hypoplasia, type 2F	4
TSEN2	Strong	Autosomal recessive	pontocerebellar hypoplasia type 2B	4
TSEN54	Strong	Autosomal recessive	pontocerebellar hypoplasia type 5	6
TSEN34	Supportive	Autosomal recessive	pontocerebellar hypoplasia type 2	5

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
TSEN34	Orphanet:2524	Pontocerebellar hypoplasia type 2
TSEN15	Orphanet:2524	Pontocerebellar hypoplasia type 2
TSEN2	Orphanet:2524	Pontocerebellar hypoplasia type 2
SEPSECS	Orphanet:247198	Progressive cerebello-cerebral atrophy
SEPSECS	Orphanet:2524	Pontocerebellar hypoplasia type 2

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSEN54	HGNC:27561	ENSG00000182173	Q7Z6J9	tRNA-splicing endonuclease subunit Sen54	gencc,clinvar
TSEN34	HGNC:15506	ENSG00000170892	Q9BSV6	tRNA-splicing endonuclease subunit Sen34	gencc
TSEN15	HGNC:16791	ENSG00000198860	Q8WW01	tRNA-splicing endonuclease subunit Sen15	gencc
TSEN2	HGNC:28422	ENSG00000154743	Q8NCE0	tRNA-splicing endonuclease subunit Sen2	gencc
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	gencc

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.
TSEN34	tRNA-splicing endonuclease subunit Sen34	Constitutes one of the two catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.
TSEN15	tRNA-splicing endonuclease subunit Sen15	Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.
TSEN2	tRNA-splicing endonuclease subunit Sen2	Constitutes one of the two catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.

Protein-family classification

Druggable: 5 · 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)	5	12.0×	4e-06

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
TSEN34	Enzyme (other)	yes	4.6.1.16	tRNA_splic, tRNA_intron_Endonuc_cat-like, tRNA_endonuc-like_dom_sf
TSEN15	Enzyme (other)	yes	4.6.1.16	tRNA_endonuc-like_dom_sf, tRNA-endonuc_su_Sen15, tRNA_intron_Endo_cat-like_sf
TSEN2	Enzyme (other)	yes	4.6.1.16	tRNA_splic, tRNA_intron_Endonuc_cat-like, tRNA_intron_Endonuc_N
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
granulocyte	1
right uterine tube	1
blood	1
right adrenal gland	1
right adrenal gland cortex	1
C1 segment of cervical spinal cord	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
buccal mucosa cell	1
mucosa of transverse colon	1
primordial germ cell in gonad	1
ileal mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	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
TSEN34	140	ubiquitous	marker	blood, right adrenal gland, right adrenal gland cortex
TSEN15	253	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, C1 segment of cervical spinal cord
TSEN2	225	ubiquitous	marker	buccal mucosa cell, mucosa of transverse colon, primordial germ cell in gonad
SEPSECS	219	ubiquitous	yes	ileal mucosa, male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SEPSECS	1,756
TSEN2	1,088
TSEN54	1,085
TSEN15	851
TSEN34	680

Intra-cohort edges

A	B	Sources
SEPSECS	TSEN15	string_interaction
SEPSECS	TSEN2	string_interaction
SEPSECS	TSEN34	string_interaction
SEPSECS	TSEN54	string_interaction
TSEN15	TSEN2	biogrid_interaction, intact, string_interaction
TSEN15	TSEN34	biogrid_interaction, intact, string_interaction
TSEN15	TSEN54	biogrid_interaction, intact, string_interaction
TSEN2	TSEN34	biogrid_interaction, intact, string_interaction
TSEN2	TSEN54	biogrid_interaction, intact, string_interaction
TSEN34	TSEN54	biogrid_interaction, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSEN15	Q8WW01	7
SEPSECS	Q9HD40	7
TSEN34	Q9BSV6	6
TSEN54	Q7Z6J9	5
TSEN2	Q8NCE0	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA processing	4	285.5×	2e-09	TSEN54, TSEN34, TSEN15, TSEN2
tRNA processing in the nucleus	4	157.5×	1e-08	TSEN54, TSEN34, TSEN15, TSEN2
Metabolism of RNA	4	33.3×	4e-06	TSEN54, TSEN34, TSEN15, TSEN2
Selenoamino acid metabolism	1	39.4×	0.044	SEPSECS
Selenocysteine synthesis	1	24.0×	0.057	SEPSECS
Metabolism of amino acids and derivatives	1	13.5×	0.084	SEPSECS
Metabolism	1	2.3×	0.362	SEPSECS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 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	3	3370.4×	8e-11	TSEN54, TSEN34, TSEN2
tRNA splicing, via endonucleolytic cleavage and ligation	3	842.6×	8e-09	TSEN54, TSEN15, TSEN2
mRNA processing	4	63.0×	3e-07	TSEN54, TSEN34, TSEN15, TSEN2
conversion of seryl-tRNAsec to selenocys-tRNAsec	1	1685.2×	9e-04	SEPSECS
selenocysteine incorporation	1	374.5×	0.003	SEPSECS
tRNA processing	1	168.5×	0.006	TSEN2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 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
TSEN34	0	0
TSEN15	0	0
TSEN2	0	0
SEPSECS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TSEN54	4.6.1.16	tRNA-intron lyase
TSEN34	4.6.1.16	tRNA-intron lyase
TSEN15	4.6.1.16	tRNA-intron lyase
TSEN2	4.6.1.16	tRNA-intron lyase
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	5	TSEN54, TSEN34, TSEN15, TSEN2, SEPSECS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TSEN54	0	—
TSEN34	0	—
TSEN15	0	—
TSEN2	0	—
SEPSECS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.