Cystic leukoencephalopathy without megalencephaly

Summary

Cystic leukoencephalopathy without megalencephaly (MONDO:0013058) is a disease caused by RNASET2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RNASET2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 58

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	cystic leukoencephalopathy without megalencephaly
Mondo ID	MONDO:0013058
MeSH	C567845
OMIM	612951
Orphanet	85136
DOID	DOID:0081007
ICD-11	1081165012
SNOMED CT	720825005
UMLS	C2751843
MedGen	416646
GARD	0013199
Is cancer (heuristic)	no

Also known as: CLWM · RNAse T2-deficient leukoencephalopathy

Data availability: 58 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › cystic leukoencephalopathy without megalencephaly

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

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

58 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 11 benign, 8 conflicting classifications of pathogenicity, 7 pathogenic, 2 likely pathogenic, 2 likely benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2217501	NM_003730.6(RNASET2):c.154C>T (p.Gln52Ter)	RNASET2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2576615	NM_003730.6(RNASET2):c.332+1G>T	RNASET2	Pathogenic	criteria provided, multiple submitters, no conflicts
412	NM_003730.6(RNASET2):c.550T>C (p.Cys184Arg)	RNASET2	Pathogenic	criteria provided, single submitter
413	NM_003730.6(RNASET2):c.87-1341_147+1181del	RNASET2	Pathogenic	no assertion criteria provided
414	NM_003730.6(RNASET2):c.262-2A>G	RNASET2	Pathogenic	no assertion criteria provided
415	NM_003730.6(RNASET2):c.332+1del	RNASET2	Pathogenic	no assertion criteria provided
416	NM_003730.6(RNASET2):c.50_64del (p.Ala17_Leu21del)	RNASET2	Pathogenic	no assertion criteria provided
872952	NM_003730.6(RNASET2):c.233C>A (p.Ser78Ter)	RNASET2	Pathogenic	criteria provided, single submitter
1098640	NM_003730.6(RNASET2):c.148-1G>T	RNASET2	Likely pathogenic	criteria provided, single submitter
3391303	NM_003730.6(RNASET2):c.195_198del (p.Gly66fs)	RNASET2	Likely pathogenic	criteria provided, single submitter
356028	NM_003730.6(RNASET2):c.652G>A (p.Glu218Lys)	RNASET2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356031	NM_003730.6(RNASET2):c.534G>A (p.Val178=)	RNASET2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356034	NM_003730.6(RNASET2):c.360C>A (p.Thr120=)	RNASET2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436545	NM_003730.6(RNASET2):c.710dup (p.Leu238fs)	RNASET2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
779708	NM_003730.6(RNASET2):c.207C>T (p.Pro69=)	RNASET2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
786739	NM_003730.6(RNASET2):c.660G>A (p.Pro220=)	RNASET2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903948	NM_003730.6(RNASET2):c.568-4T>C	RNASET2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907287	NM_003730.6(RNASET2):c.648G>C (p.Pro216=)	RNASET2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356046	NM_003730.6(RNASET2):c.-176C>T	LOC129997675	Uncertain significance	criteria provided, single submitter
356048	NM_003730.6(RNASET2):c.-203G>A	LOC129997675	Uncertain significance	criteria provided, single submitter
356050	NM_003730.6(RNASET2):c.-251G>C	LOC129997675	Uncertain significance	criteria provided, single submitter
2435443	NM_003730.6(RNASET2):c.394AAG[1] (p.Lys133del)	RNASET2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435444	NM_003730.6(RNASET2):c.705C>A (p.Ser235Arg)	RNASET2	Uncertain significance	criteria provided, single submitter
2435445	NM_003730.6(RNASET2):c.261+3A>G	RNASET2	Uncertain significance	criteria provided, single submitter
2435446	NM_003730.6(RNASET2):c.502T>C (p.Phe168Leu)	RNASET2	Uncertain significance	criteria provided, multiple submitters, no conflicts
356033	NM_003730.6(RNASET2):c.380C>T (p.Ala127Val)	RNASET2	Uncertain significance	criteria provided, single submitter
356035	NM_003730.6(RNASET2):c.325C>A (p.Arg109Ser)	RNASET2	Uncertain significance	criteria provided, single submitter
356036	NM_003730.6(RNASET2):c.224G>A (p.Cys75Tyr)	RNASET2	Uncertain significance	criteria provided, single submitter
356041	NM_003730.6(RNASET2):c.-14C>A	RNASET2	Uncertain significance	criteria provided, single submitter
356042	NM_003730.6(RNASET2):c.-32A>G	RNASET2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
RNASET2	Definitive	Autosomal recessive	cystic leukoencephalopathy without megalencephaly	6
NDUFA2	Supportive	Autosomal recessive	cystic leukoencephalopathy without megalencephaly	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNASET2	Orphanet:85136	Cystic leukoencephalopathy without megalencephaly
NDUFA2	Orphanet:85136	Cystic leukoencephalopathy without megalencephaly

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
RNASET2	HGNC:21686	ENSG00000026297	O00584	Ribonuclease T2	gencc,clinvar
NDUFA2	HGNC:7685	ENSG00000131495	O43678	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNASET2	Ribonuclease T2	Ribonuclease that plays an essential role in innate immune response by recognizing and degrading RNAs from microbial pathogens that are subsequently sensed by TLR8.
NDUFA2	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNASET2	Enzyme (other)	yes	4.6.1.19	RNase_T2-like, RNase_T2_His_AS_1, RNase_T2_His_AS_2
NDUFA2	Other/Unknown	no		Ribosomal_mL43/mS25/NADH_DH, NADH_Ub_cplx-1_asu_su-2, Thioredoxin-like_sf

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
blood	1
granulocyte	1
right uterine tube	1
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNASET2	291	ubiquitous	marker	right uterine tube, granulocyte, blood
NDUFA2	300	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFA2	3,304
RNASET2	1,061

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFA2	O43678	8
RNASET2	O00584	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Complex I biogenesis	1	82.8×	0.051	NDUFA2
Mitochondrial protein degradation	1	57.1×	0.051	NDUFA2
Respiratory electron transport	1	47.6×	0.051	NDUFA2
Aerobic respiration and respiratory electron transport	1	44.3×	0.051	NDUFA2
Innate Immune System	1	12.8×	0.127	RNASET2
Neutrophil degranulation	1	11.5×	0.127	RNASET2
Immune System	1	6.5×	0.165	RNASET2
Metabolism of proteins	1	6.2×	0.165	NDUFA2
Metabolism	1	5.8×	0.165	NDUFA2

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
blastocyst hatching	1	271.8×	0.010	NDUFA2
RNA catabolic process	1	227.7×	0.010	RNASET2
mitochondrial electron transport, NADH to ubiquinone	1	179.3×	0.010	NDUFA2
proton motive force-driven mitochondrial ATP synthesis	1	131.7×	0.010	NDUFA2
aerobic respiration	1	123.9×	0.010	NDUFA2
innate immune response	1	16.8×	0.059	RNASET2

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
RNASET2	0	0
NDUFA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NDUFA2	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNASET2	4.6.1.19	ribonuclease T2

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	1	RNASET2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NDUFA2

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)
RNASET2	0	—
NDUFA2	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.