Hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome

Summary

Hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome (MONDO:0018655) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1

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

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome
Mondo ID	MONDO:0018655
Orphanet	447893
UMLS	C5681201
MedGen	1842862
GARD	0017773
Is cancer (heuristic)	no

Data availability: 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › POLR3A-related disorder › leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism › hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome

Related subtypes (3): tremor-ataxia-central hypomyelination syndrome, odontoleukodystrophy, hypomyelinating leukodystrophy-ataxia-hypodontia-hypomyelination syndrome

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · 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
POLR3A	Supportive	Autosomal recessive	hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLR3A	Orphanet:137639	Hypomyelinating leukodystrophy-ataxia-hypodontia-hypomyelination syndrome
POLR3A	Orphanet:3455	Wiedemann-Rautenstrauch syndrome
POLR3A	Orphanet:447893	Hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome
POLR3A	Orphanet:447896	Tremor-ataxia-central hypomyelination syndrome
POLR3A	Orphanet:77295	Odontoleukodystrophy
POLR3A	Orphanet:88637	Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

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
POLR3A	HGNC:30074	ENSG00000148606	O14802	DNA-directed RNA polymerase III subunit RPC1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLR3A	DNA-directed RNA polymerase III subunit RPC1	Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLR3A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3

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
buccal mucosa cell	1
middle temporal gyrus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLR3A	242	ubiquitous	marker	buccal mucosa cell, middle temporal gyrus, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR3A	4,915

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR3A	O14802	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
RNA Polymerase III Chain Elongation	1	634.4×	0.005	POLR3A
RNA Polymerase III Transcription Termination	1	496.5×	0.005	POLR3A
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	423.0×	0.005	POLR3A
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	407.9×	0.005	POLR3A
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	407.9×	0.005	POLR3A
RNA Polymerase III Transcription Initiation	1	335.9×	0.005	POLR3A
RNA Polymerase III Transcription	1	326.3×	0.005	POLR3A
Cytosolic sensors of pathogen-associated DNA	1	285.5×	0.005	POLR3A
RNA Polymerase III Abortive And Retractive Initiation	1	278.5×	0.005	POLR3A
Innate Immune System	1	25.5×	0.047	POLR3A
Gene expression (Transcription)	1	17.8×	0.061	POLR3A
Immune System	1	13.0×	0.077	POLR3A

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 transcription by RNA polymerase III	1	1532.0×	0.003	POLR3A
positive regulation of interferon-beta production	1	391.9×	0.006	POLR3A
DNA-templated transcription	1	224.7×	0.007	POLR3A
defense response to virus	1	69.3×	0.018	POLR3A
innate immune response	1	33.6×	0.030	POLR3A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLR3A	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	POLR3A

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)
POLR3A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.