Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism

Summary

Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (MONDO:0011897) is a disease caused by POLR3A (GenCC Strong), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: POLR3A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 309
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism
Mondo ID	MONDO:0011897
OMIM	607694
Orphanet	137639
DOID	DOID:0060794
SNOMED CT	721846006
GARD	0016948
Is cancer (heuristic)	no

Also known as: 4H syndrome · HLD7 · hypomyelinating leukodystrophy 7 with or without oligodontia and-or hypogonadotropic hypogonadism · leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism · leukodystrophy, hypomyelinating, with hypodontia and hypogonadotropic hypogonadism · leukoencephalopathy, hypomyelinating, with ataxia and delayed dentition

Data availability: 309 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

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

Related subtypes (1): Wiedemann-Rautenstrauch syndrome

Subtypes (4): hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, 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

ClinVar germline variants

309 retrieved; paginated sample, class counts are floors:

113 uncertain significance, 54 conflicting classifications of pathogenicity, 32 benign, 23 pathogenic/likely pathogenic, 22 benign/likely benign, 20 likely pathogenic, 19 not provided, 15 pathogenic, 11 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
619038	NM_007055.4(POLR3A):c.3243-2A>G	LOC126860970	Pathogenic	criteria provided, multiple submitters, no conflicts
1030186	NM_007055.4(POLR3A):c.3733C>T (p.Arg1245Ter)	POLR3A	Pathogenic	criteria provided, multiple submitters, no conflicts
1034345	NM_007055.4(POLR3A):c.2323_2329del (p.Asn775fs)	POLR3A	Pathogenic	criteria provided, multiple submitters, no conflicts
1184058	NM_007055.4(POLR3A):c.441dup (p.Asp148Ter)	POLR3A	Pathogenic	criteria provided, single submitter
1385211	NM_007055.4(POLR3A):c.1393C>T (p.Gln465Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1879069	NM_007055.4(POLR3A):c.646-665_1185+867del	POLR3A	Pathogenic	criteria provided, single submitter
280111	NM_007055.4(POLR3A):c.1740dup (p.Val581fs)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31143	NM_007055.4(POLR3A):c.2015G>A (p.Gly672Glu)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31144	NM_007055.4(POLR3A):c.1909+18G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31145	NM_007055.4(POLR3A):c.2554A>G (p.Met852Val)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31146	NM_007055.4(POLR3A):c.2617-1G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31147	NM_007055.4(POLR3A):c.418C>T (p.Arg140Ter)	POLR3A	Pathogenic	criteria provided, single submitter
31148	NM_007055.4(POLR3A):c.2690T>A (p.Ile897Asn)	POLR3A	Pathogenic	no assertion criteria provided
31149	NM_007055.4(POLR3A):c.3013C>T (p.Arg1005Cys)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3254641	NM_007055.4(POLR3A):c.2212C>T (p.Gln738Ter)	POLR3A	Pathogenic	criteria provided, single submitter
41243	NM_007055.4(POLR3A):c.2171G>A (p.Cys724Tyr)	POLR3A	Pathogenic	criteria provided, single submitter
41245	NM_007055.4(POLR3A):c.2830G>T (p.Glu944Ter)	POLR3A	Pathogenic	criteria provided, single submitter
430255	NM_007055.4(POLR3A):c.2119C>T (p.Gln707Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
436361	NM_007055.4(POLR3A):c.3243-1G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
445922	NM_007055.4(POLR3A):c.1909+22G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449556	NM_007055.4(POLR3A):c.1771-7C>G	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549559	NM_007055.4(POLR3A):c.3337-11T>C	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549560	NM_007055.4(POLR3A):c.1048+5G>T	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549565	NM_007055.4(POLR3A):c.3G>T (p.Met1Ile)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617891	NM_007055.4(POLR3A):c.2005C>T (p.Arg669Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617894	NM_007055.4(POLR3A):c.760C>T (p.Arg254Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619037	NM_007055.4(POLR3A):c.1572+1G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
638561	NM_007055.4(POLR3A):c.2325C>G (p.Asn775Lys)	POLR3A	Pathogenic	no assertion criteria provided
684772	NM_007055.4(POLR3A):c.1681C>T (p.Arg561Ter)	POLR3A	Pathogenic	criteria provided, single submitter
684773	NM_007055.4(POLR3A):c.1051C>T (p.Arg351Ter)	POLR3A	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 8 · 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	Strong	Autosomal recessive	leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism	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
POLR3B	Orphanet:85186	Endosteal sclerosis-cerebellar hypoplasia syndrome
POLR3B	Orphanet:88637	Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLR3A	HGNC:30074	ENSG00000148606	O14802	DNA-directed RNA polymerase III subunit RPC1	gencc,clinvar
POLR3B	HGNC:30348	ENSG00000013503	Q9NW08	DNA-directed RNA polymerase III subunit RPC2	clinvar

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.
POLR3B	DNA-directed RNA polymerase III subunit RPC2	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: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLR3A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3
POLR3B	Other/Unknown	no		DNA-dir_RNAP_su2_dom, RNA_pol_bsu_CS, RNA_pol_Rpb2_7

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	2
buccal mucosa cell	1
middle temporal gyrus	1
endothelial cell	1
esophagus squamous epithelium	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
POLR3B	247	ubiquitous	marker	secondary oocyte, esophagus squamous epithelium, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR3B	5,712
POLR3A	4,915

Intra-cohort edges

A	B	Sources
POLR3A	POLR3B	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR3A	O14802	29
POLR3B	Q9NW08	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 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
RNA Polymerase III Chain Elongation	2	634.4×	1e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Termination	2	496.5×	1e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation From Type 2 Promoter	2	423.0×	1e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation From Type 1 Promoter	2	407.9×	1e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation From Type 3 Promoter	2	407.9×	1e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation	2	335.9×	2e-05	POLR3A, POLR3B
RNA Polymerase III Transcription	2	326.3×	2e-05	POLR3A, POLR3B
Cytosolic sensors of pathogen-associated DNA	2	285.5×	2e-05	POLR3A, POLR3B
RNA Polymerase III Abortive And Retractive Initiation	2	278.5×	2e-05	POLR3A, POLR3B
Innate Immune System	2	25.5×	0.002	POLR3A, POLR3B
Gene expression (Transcription)	2	17.8×	0.003	POLR3A, POLR3B
Immune System	2	13.0×	0.006	POLR3A, POLR3B

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of interferon-beta production	2	391.9×	4e-05	POLR3A, POLR3B
defense response to virus	2	69.3×	7e-04	POLR3A, POLR3B
snRNA transcription by RNA polymerase III	1	936.2×	0.002	POLR3B
tRNA transcription by RNA polymerase III	1	766.0×	0.002	POLR3A
innate immune response	2	33.6×	0.002	POLR3A, POLR3B
positive regulation of innate immune response	1	263.3×	0.004	POLR3B
DNA-templated transcription	1	112.3×	0.009	POLR3A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
POLR3B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	POLR3A, POLR3B

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)
POLR3A	0	—
POLR3B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies