pontocerebellar hypoplasia, type 1C

Summary

pontocerebellar hypoplasia, type 1C (MONDO:0014485) is a disease caused by EXOSC8 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: EXOSC8 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia, type 1C
Mondo ID	MONDO:0014485
OMIM	616081
DOID	DOID:0112334
UMLS	C4015160
MedGen	863597
GARD	0016058
Is cancer (heuristic)	no

Also known as: EXOSC8 pontocerebellar hypoplasia type 1 · PCH1C · pontocerebellar hypoplasia type 1 caused by mutation in EXOSC8 · pontocerebellar hypoplasia, type 1C

Data availability: 15 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › pontocerebellar hypoplasia type 1 › pontocerebellar hypoplasia, type 1C

Related subtypes (2): pontocerebellar hypoplasia type 1A, pontocerebellar hypoplasia type 1B

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

15 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 4 conflicting classifications of pathogenicity, 1 pathogenic, 1 benign/likely benign, 1 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
157609	NM_181503.3(EXOSC8):c.5C>T (p.Ala2Val)	EXOSC8	Pathogenic	no assertion criteria provided
4845689	NM_181503.3(EXOSC8):c.259delinsTGG (p.Pro87fs)	EXOSC8	Likely pathogenic	criteria provided, single submitter
1027899	NM_181503.3(EXOSC8):c.13T>C (p.Phe5Leu)	EXOSC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157608	NM_181503.3(EXOSC8):c.815G>C (p.Ser272Thr)	EXOSC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
870726	NM_181503.3(EXOSC8):c.89_91del (p.Gly30del)	EXOSC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
870727	NM_181503.3(EXOSC8):c.734dup (p.Ala246fs)	EXOSC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2185125	NM_181503.3(EXOSC8):c.540_544del (p.Asn180fs)	EXOSC8	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441309	NM_181503.3(EXOSC8):c.241C>T (p.Pro81Ser)	EXOSC8	Uncertain significance	criteria provided, single submitter
3238835	NM_181503.3(EXOSC8):c.628C>A (p.Pro210Thr)	EXOSC8	Uncertain significance	criteria provided, single submitter
3242109	NM_181503.3(EXOSC8):c.17+5del	EXOSC8	Uncertain significance	criteria provided, single submitter
548522	NM_181503.3(EXOSC8):c.781G>T (p.Glu261Ter)	EXOSC8	Uncertain significance	criteria provided, single submitter
813914	NM_181503.3(EXOSC8):c.17+1G>T	EXOSC8	Uncertain significance	criteria provided, single submitter
813915	NM_181503.3(EXOSC8):c.695T>C (p.Leu232Pro)	EXOSC8	Uncertain significance	criteria provided, single submitter
235309	NM_181503.3(EXOSC8):c.55-10_55-9del	EXOSC8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
802960	NM_181503.3(EXOSC8):c.321G>A (p.Gln107=)	EXOSC8	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
EXOSC8	Strong	Autosomal recessive	pontocerebellar hypoplasia, type 1C	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EXOSC8	Orphanet:2254	Pontocerebellar hypoplasia type 1

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
EXOSC8	HGNC:17035	ENSG00000120699	Q96B26	Exosome complex component RRP43	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EXOSC8	Exosome complex component RRP43	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.

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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EXOSC8	Scaffold/PPI	no		ExoRNase_PH_dom1, ExoRNase_PH_dom2, Ribosomal_Su5_D2-typ_SF

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
ganglionic eminence	1
right uterine tube	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EXOSC8	298	ubiquitous	marker	ventricular zone, ganglionic eminence, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EXOSC8	2,862

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EXOSC8	Q96B26	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
mRNA decay by 3’ to 5’ exoribonuclease	1	713.8×	0.003	EXOSC8
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	1	634.4×	0.003	EXOSC8
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	1	634.4×	0.003	EXOSC8
KSRP (KHSRP) binds and destabilizes mRNA	1	634.4×	0.003	EXOSC8
ATF4 activates genes in response to endoplasmic reticulum stress	1	407.9×	0.003	EXOSC8
Nuclear RNA decay	1	308.6×	0.004	EXOSC8
Major pathway of rRNA processing in the nucleolus and cytosol	1	61.7×	0.016	EXOSC8

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
U1 snRNA 3’-end processing	1	5617.3×	8e-04	EXOSC8
U5 snRNA 3’-end processing	1	5617.3×	8e-04	EXOSC8
exonucleolytic trimming to generate mature 3’-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	2407.4×	8e-04	EXOSC8
nuclear polyadenylation-dependent rRNA catabolic process	1	2407.4×	8e-04	EXOSC8
TRAMP-dependent tRNA surveillance pathway	1	2407.4×	8e-04	EXOSC8
U4 snRNA 3’-end processing	1	2106.5×	8e-04	EXOSC8
nuclear mRNA surveillance	1	1872.4×	8e-04	EXOSC8
rRNA catabolic process	1	991.3×	0.001	EXOSC8
RNA catabolic process	1	455.5×	0.002	EXOSC8
RNA processing	1	218.9×	0.005	EXOSC8

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
EXOSC8	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	EXOSC8

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)
EXOSC8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.