Leukodystrophy, hypomyelinating, 15

Summary

Leukodystrophy, hypomyelinating, 15 (MONDO:0054782) is a disease caused by EPRS1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: EPRS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukodystrophy, hypomyelinating, 15
Mondo ID	MONDO:0054782
OMIM	617951
DOID	DOID:0070398
UMLS	C4693733
MedGen	1633653
GARD	0025975
Is cancer (heuristic)	no

Also known as: HLD15 · leukodystrophy, hypomyelinating, 15

Data availability: 35 ClinVar variants · 3 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 › leukodystrophy, hypomyelinating, 15

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, cystic leukoencephalopathy without megalencephaly, 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, 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

35 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 5 benign, 5 pathogenic, 3 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1334631	NM_004446.3(EPRS1):c.3832C>T (p.Arg1278Ter)	EPRS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2865970	NM_004446.3(EPRS1):c.2953C>T (p.Gln985Ter)	EPRS1	Pathogenic	criteria provided, multiple submitters, no conflicts
523134	NM_004446.3(EPRS1):c.1015C>T (p.Arg339Ter)	EPRS1	Pathogenic	no assertion criteria provided
523135	NM_004446.3(EPRS1):c.3478C>T (p.Pro1160Ser)	EPRS1	Pathogenic	no assertion criteria provided
523136	NM_004446.3(EPRS1):c.3667del (p.Thr1223fs)	EPRS1	Pathogenic	no assertion criteria provided
523137	NM_004446.3(EPRS1):c.3377T>C (p.Met1126Thr)	EPRS1	Pathogenic	no assertion criteria provided
3069175	NM_004446.3(EPRS1):c.4444C>A (p.Pro1482Thr)	EPRS1	Likely pathogenic	criteria provided, single submitter
1028244	NM_004446.3(EPRS1):c.3215G>A (p.Gly1072Asp)	EPRS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1680924	NM_004446.3(EPRS1):c.2747G>A (p.Arg916Gln)	EPRS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523133	NM_004446.3(EPRS1):c.3344C>G (p.Pro1115Arg)	EPRS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028241	NM_004446.3(EPRS1):c.2372A>G (p.Tyr791Cys)	EPRS1	Uncertain significance	criteria provided, single submitter
1028242	NM_004446.3(EPRS1):c.2702C>T (p.Ala901Val)	EPRS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028243	NM_004446.3(EPRS1):c.2789T>C (p.Ile930Thr)	EPRS1	Uncertain significance	criteria provided, single submitter
1028245	NM_004446.3(EPRS1):c.3972T>G (p.Ile1324Met)	EPRS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028246	NM_004446.3(EPRS1):c.4244+3A>C	EPRS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031422	NM_004446.3(EPRS1):c.3782T>C (p.Ile1261Thr)	EPRS1	Uncertain significance	criteria provided, single submitter
1805778	NM_004446.3(EPRS1):c.3404A>C (p.Gln1135Pro)	EPRS1	Uncertain significance	criteria provided, single submitter
2176519	NM_004446.3(EPRS1):c.4067A>G (p.Asn1356Ser)	EPRS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441273	NM_004446.3(EPRS1):c.4361A>G (p.Glu1454Gly)	EPRS1	Uncertain significance	criteria provided, single submitter
2441274	NM_004446.3(EPRS1):c.2929A>G (p.Lys977Glu)	EPRS1	Uncertain significance	criteria provided, single submitter
2441936	NM_004446.3(EPRS1):c.1399A>G (p.Thr467Ala)	EPRS1	Uncertain significance	criteria provided, single submitter
2664966	NM_004446.3(EPRS1):c.641A>G (p.His214Arg)	EPRS1	Uncertain significance	criteria provided, single submitter
2664967	NM_004446.3(EPRS1):c.619A>T (p.Ser207Cys)	EPRS1	Uncertain significance	criteria provided, single submitter
2987688	NM_004446.3(EPRS1):c.3161A>C (p.Tyr1054Ser)	EPRS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065216	NM_004446.3(EPRS1):c.3289T>G (p.Phe1097Val)	EPRS1	Uncertain significance	criteria provided, single submitter
3068299	NM_004446.3(EPRS1):c.3370A>G (p.Thr1124Ala)	EPRS1	Uncertain significance	criteria provided, single submitter
3731471	NM_004446.3(EPRS1):c.1434+5G>A	EPRS1	Uncertain significance	criteria provided, single submitter
800724	NM_004446.3(EPRS1):c.3148C>T (p.Arg1050Cys)	EPRS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
800725	NM_004446.3(EPRS1):c.3344C>T (p.Pro1115Leu)	EPRS1	Uncertain significance	criteria provided, single submitter
800786	NM_004446.3(EPRS1):c.2513G>A (p.Arg838His)	EPRS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
EPRS1	Strong	Autosomal recessive	leukodystrophy, hypomyelinating, 15	3

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
EPRS1	HGNC:3418	ENSG00000136628	P07814	Bifunctional glutamate/proline–tRNA ligase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EPRS1	Bifunctional glutamate/proline–tRNA ligase	Multifunctional protein which primarily functions within the aminoacyl-tRNA synthetase multienzyme complex, also known as multisynthetase complex.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EPRS1	Enzyme (other)	yes	6.1.1.15	WHEP-TRS_dom, Glu/Gln-tRNA-synth, aa-tRNA-synth_I_CS

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
cortical plate	1
cranial nerve II	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EPRS1	295	ubiquitous	marker	parotid gland, cranial nerve II, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPRS1	7,775

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPRS1	P07814	33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Cytosolic tRNA aminoacylation	1	439.2×	0.011	EPRS1
tRNA processing	1	356.9×	0.011	EPRS1
tRNA modification in the nucleus and cytosol	1	292.8×	0.011	EPRS1
tRNA Aminoacylation	1	285.5×	0.011	EPRS1
Selenoamino acid metabolism	1	196.9×	0.012	EPRS1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.012	EPRS1
MITF-M-regulated melanocyte development	1	114.2×	0.016	EPRS1
Metabolism of amino acids and derivatives	1	67.6×	0.023	EPRS1
Translation	1	62.1×	0.023	EPRS1
Metabolism of RNA	1	41.7×	0.031	EPRS1
Developmental Biology	1	14.5×	0.082	EPRS1
Metabolism of proteins	1	12.4×	0.086	EPRS1
Metabolism	1	11.6×	0.086	EPRS1

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
regulation of long-chain fatty acid import into cell	1	16852.0×	3e-04	EPRS1
glutamyl-tRNA aminoacylation	1	8426.0×	3e-04	EPRS1
prolyl-tRNA aminoacylation	1	8426.0×	3e-04	EPRS1
tRNA aminoacylation for protein translation	1	842.6×	0.002	EPRS1
cellular response to type II interferon	1	208.1×	0.006	EPRS1
negative regulation of translation	1	195.9×	0.006	EPRS1
cellular response to insulin stimulus	1	170.2×	0.006	EPRS1

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
EPRS1	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
EPRS1	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPRS1	6.1.1.15, 6.1.1.17	proline-tRNA ligase, glutamate-tRNA ligase

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	1	EPRS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
EPRS1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.