Hypomyelinating leukodystrophy 11

Summary

Hypomyelinating leukodystrophy 11 (MONDO:0014666) is a disease caused by POLR1C (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: POLR1C (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 66

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelinating leukodystrophy 11
Mondo ID	MONDO:0014666
OMIM	616494
DOID	DOID:0060792
UMLS	C4225305
MedGen	897960
GARD	0018088
Is cancer (heuristic)	no

Also known as: HLD11 · hypomyelinating leukodystrophy type 11 · leukodystrophy caused by mutation in POLR1C · leukodystrophy, hypomyelinating, 11 · leukodystrophy, hypomyelinating, type 11 · POLR1C leukodystrophy

Data availability: 66 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › POLR1C-related disorder › hypomyelinating leukodystrophy 11

Related subtypes (1): Treacher Collins syndrome 3

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

66 retrieved; paginated sample, class counts are floors:

16 likely pathogenic, 15 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 12 pathogenic, 11 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
635139	NM_203290.4(POLR1C):c.69+1G>A	LOC129996517	Pathogenic	criteria provided, single submitter
1368238	NM_203290.4(POLR1C):c.232C>T (p.Arg78Ter)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676483	NM_203290.4(POLR1C):c.208dup (p.Ala70fs)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204588	NM_203290.4(POLR1C):c.95A>T (p.Asn32Ile)	POLR1C	Pathogenic	criteria provided, single submitter
204589	NM_203290.4(POLR1C):c.436T>C (p.Cys146Arg)	POLR1C	Pathogenic	criteria provided, single submitter
204591	NM_203290.4(POLR1C):c.77C>T (p.Thr26Ile)	POLR1C	Pathogenic	criteria provided, multiple submitters, no conflicts
204592	NM_203290.4(POLR1C):c.326G>A (p.Arg109His)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225445	NM_203290.4(POLR1C):c.525del (p.Thr174_Trp175insTer)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280457	NM_203290.4(POLR1C):c.70-1G>A	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280857	NM_203290.4(POLR1C):c.699C>G (p.Tyr233Ter)	POLR1C	Pathogenic	criteria provided, multiple submitters, no conflicts
30811	NM_203290.4(POLR1C):c.836G>A (p.Arg279Gln)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30815	NM_203290.4(POLR1C):c.835C>T (p.Arg279Trp)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375402	NM_203290.4(POLR1C):c.88C>T (p.Pro30Ser)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375403	NM_203290.4(POLR1C):c.614del (p.Gly205fs)	POLR1C	Pathogenic	no assertion criteria provided
635140	NM_203290.4(POLR1C):c.281T>C (p.Val94Ala)	POLR1C	Pathogenic	criteria provided, single submitter
635141	NM_203290.4(POLR1C):c.313A>T (p.Ile105Phe)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635143	NM_203290.4(POLR1C):c.325C>T (p.Arg109Cys)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635144	NM_203290.4(POLR1C):c.349G>C (p.Ala117Pro)	POLR1C	Pathogenic	criteria provided, single submitter
635146	NM_203290.4(POLR1C):c.461_462del (p.Lys154fs)	POLR1C	Pathogenic	criteria provided, single submitter
635147	NM_203290.4(POLR1C):c.502G>A (p.Val168Met)	POLR1C	Pathogenic	criteria provided, single submitter
635148	NM_203290.4(POLR1C):c.616del (p.Gln206fs)	POLR1C	Pathogenic	criteria provided, multiple submitters, no conflicts
635150	NM_203290.4(POLR1C):c.785T>C (p.Ile262Thr)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635151	NM_203290.4(POLR1C):c.916_920del (p.Tyr306fs)	POLR1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635153	NM_203290.4(POLR1C):c.970G>A (p.Glu324Lys)	POLR1C	Pathogenic	criteria provided, single submitter
3593631	NM_203290.4(POLR1C):c.53del (p.Glu18fs)	LOC129996517	Likely pathogenic	criteria provided, single submitter
1324948	NM_203290.4(POLR1C):c.793C>T (p.Gln265Ter)	POLR1C	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593632	NM_203290.4(POLR1C):c.70-2A>G	POLR1C	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593634	NM_203290.4(POLR1C):c.243_246del (p.Ala82fs)	POLR1C	Likely pathogenic	criteria provided, single submitter
3593635	NM_203290.4(POLR1C):c.247G>T (p.Glu83Ter)	POLR1C	Likely pathogenic	criteria provided, single submitter
3593636	NM_203290.4(POLR1C):c.250-8_253delinsA	POLR1C	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
POLR1C	Strong	Autosomal recessive	hypomyelinating leukodystrophy 11	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLR1C	Orphanet:861	Treacher-Collins syndrome
POLR1C	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
POLR1C	HGNC:20194	ENSG00000171453	O15160	DNA-directed RNA polymerases I and III subunit RPAC1	gencc,clinvar
SLC35B2	HGNC:16872	ENSG00000157593	Q8TB61	Adenosine 3’-phospho 5’-phosphosulfate transporter 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLR1C	DNA-directed RNA polymerases I and III subunit RPAC1	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
SLC35B2	Adenosine 3’-phospho 5’-phosphosulfate transporter 1	Probably functions as a 3’-phosphoadenylyl sulfate:adenosine 3’,5’-bisphosphate antiporter at the Golgi membranes.

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)
POLR1C	Other/Unknown	no		DNA-dir_RNA_pol_30-40kDasu_CS, DNA-dir_RNA_pol_insert, DNA-dir_RNA_pol_RpoA/D/Rpb3
SLC35B2	Other/Unknown	no		HUT1, EmrE-like

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
cervix squamous epithelium	1
secondary oocyte	1
sperm	1
islet of Langerhans	1
primordial germ cell in gonad	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLR1C	286	ubiquitous	marker	secondary oocyte, sperm, cervix squamous epithelium
SLC35B2	134	ubiquitous	marker	stromal cell of endometrium, primordial germ cell in gonad, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR1C	5,495
SLC35B2	1,604

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR1C	O15160	36

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC35B2	Q8TB61	81.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. 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
Transport and metabolism of PAPS	1	815.7×	0.013	SLC35B2
Transport of nucleotide sugars	1	571.0×	0.013	SLC35B2
RNA Polymerase III Chain Elongation	1	317.2×	0.013	POLR1C
Cytosolic sulfonation of small molecules	1	259.6×	0.013	SLC35B2
RNA Polymerase III Transcription Termination	1	248.3×	0.013	POLR1C
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	211.5×	0.013	POLR1C
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	203.9×	0.013	POLR1C
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	203.9×	0.013	POLR1C
Positive epigenetic regulation of rRNA expression	1	173.0×	0.013	POLR1C
RNA Polymerase III Transcription Initiation	1	167.9×	0.013	POLR1C
RNA Polymerase I Transcription Termination	1	163.1×	0.013	POLR1C
RNA Polymerase III Transcription	1	163.1×	0.013	POLR1C
RNA Polymerase I Promoter Clearance	1	146.4×	0.013	POLR1C
Cytosolic sensors of pathogen-associated DNA	1	142.8×	0.013	POLR1C
RNA Polymerase I Transcription	1	142.8×	0.013	POLR1C
Phase II - Conjugation of compounds	1	139.3×	0.013	SLC35B2
RNA Polymerase III Abortive And Retractive Initiation	1	139.3×	0.013	POLR1C
Transport of vitamins, nucleosides, and related molecules	1	135.9×	0.013	SLC35B2
Negative epigenetic regulation of rRNA expression	1	129.8×	0.013	POLR1C
RNA Polymerase I Transcription Initiation	1	112.0×	0.014	POLR1C
Glycosaminoglycan metabolism	1	109.8×	0.014	SLC35B2
Biological oxidations	1	64.9×	0.022	SLC35B2
B-WICH complex positively regulates rRNA expression	1	60.7×	0.022	POLR1C
RNA Polymerase I Promoter Escape	1	60.7×	0.022	POLR1C
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.022	SLC35B2
NoRC negatively regulates rRNA expression	1	52.4×	0.024	POLR1C
Epigenetic regulation of gene expression	1	35.7×	0.034	POLR1C
SLC-mediated transmembrane transport	1	29.6×	0.040	SLC35B2
Innate Immune System	1	12.8×	0.086	POLR1C
Transport of small molecules	1	12.6×	0.086	SLC35B2

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
3’-phosphoadenosine 5’-phosphosulfate transport	1	4213.0×	7e-04	SLC35B2
5’-adenylyl sulfate transmembrane transport	1	4213.0×	7e-04	SLC35B2
transcription by RNA polymerase I	1	702.2×	0.003	POLR1C
chondroitin sulfate proteoglycan biosynthetic process	1	312.1×	0.005	SLC35B2
transmembrane transport	1	84.3×	0.014	SLC35B2
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.027	SLC35B2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
POLR1C	1	2
SLC35B2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	POLR1C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
POLR1C	7	Binding:7
SLC35B2	1	Binding:1

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	POLR1C

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	1	POLR1C
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC35B2

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)
SLC35B2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.