Hypomyelinating leukodystrophy 9

Summary

Hypomyelinating leukodystrophy 9 (MONDO:0014506) is a disease caused by RARS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RARS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 39
• Phenotypes (HPO): 27

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

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000817	Reduced eye contact	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0006808	Cerebral hypomyelination	Frequent (30-79%)
HP:0006895	Lower limb hypertonia	Frequent (30-79%)
HP:0007153	Progressive extrapyramidal movement disorder	Frequent (30-79%)
HP:0007281	Developmental stagnation	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002151	Increased circulating lactate concentration	Occasional (5-29%)
HP:0002506	Diffuse cerebral atrophy	Occasional (5-29%)
HP:0007024	Pseudobulbar paralysis	Occasional (5-29%)
HP:0007179	Absent smooth pursuit	Occasional (5-29%)
HP:0007359	Focal-onset seizure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelinating leukodystrophy 9
Mondo ID	MONDO:0014506
OMIM	616140
Orphanet	438114
DOID	DOID:0060791
UMLS	C4015323
MedGen	863760
GARD	0017734
Is cancer (heuristic)	no

Also known as: HLD9 · hypomyelinating leukodystrophy type 9 · leukodystrophy caused by mutation in RARS · leukodystrophy, hypomyelinating, 9 · leukodystrophy, hypomyelinating, type 9 · RARS leukodystrophy · RARS-related autosomal recessive hypomyelinating leukodystrophy

Data availability: 39 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 › hypomyelinating leukodystrophy 9

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, 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

39 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 6 benign, 6 pathogenic, 4 conflicting classifications of pathogenicity, 4 likely pathogenic, 3 pathogenic/likely pathogenic, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
162080	NM_002887.4(RARS1):c.5A>G (p.Asp2Gly)	RARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
162081	NM_002887.4(RARS1):c.45+1G>T	RARS1	Pathogenic	no assertion criteria provided
162082	NM_002887.4(RARS1):c.96_97del (p.Cys32fs)	RARS1	Pathogenic	no assertion criteria provided
162083	NM_002887.4(RARS1):c.1A>G (p.Met1Val)	RARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
162084	NM_002887.4(RARS1):c.1535G>A (p.Arg512Gln)	RARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384892	NM_002887.4(RARS1):c.999del (p.Glu335fs)	RARS1	Pathogenic	criteria provided, single submitter
391980	NM_002887.4(RARS1):c.2T>C (p.Met1Thr)	RARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424864	NM_002887.4(RARS1):c.1846_1847del (p.Tyr616fs)	RARS1	Pathogenic	no assertion criteria provided
871624	NM_002887.4(RARS1):c.1452+1G>A	RARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324988	NM_002887.4(RARS1):c.614_615del (p.Lys205fs)	RARS1	Likely pathogenic	criteria provided, single submitter
2683827	NM_002887.4(RARS1):c.1716G>A (p.Trp572Ter)	RARS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3780529	NM_002887.4(RARS1):c.639del (p.Arg213fs)	RARS1	Likely pathogenic	criteria provided, single submitter
977922	NM_002887.4(RARS1):c.1316C>A (p.Ala439Asp)	RARS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030601	NM_002887.4(RARS1):c.793C>T (p.Pro265Ser)	RARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033549	NM_002887.4(RARS1):c.36G>C (p.Leu12=)	RARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1254187	NM_002887.4(RARS1):c.206C>T (p.Pro69Leu)	RARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265854	NM_002887.4(RARS1):c.1367C>T (p.Ser456Leu)	RARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029653	NM_002887.4(RARS1):c.11T>A (p.Leu4Gln)	RARS1	Uncertain significance	criteria provided, single submitter
1029654	NM_002887.4(RARS1):c.161G>A (p.Arg54Gln)	RARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030600	NM_002887.4(RARS1):c.1816A>T (p.Thr606Ser)	RARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030602	NM_002887.4(RARS1):c.860A>G (p.Lys287Arg)	RARS1	Uncertain significance	criteria provided, single submitter
1680407	NM_002887.4(RARS1):c.272C>T (p.Ala91Val)	RARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1680449	NM_002887.4(RARS1):c.1912T>A (p.Cys638Ser)	RARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1906269	NM_002887.4(RARS1):c.1522C>A (p.Leu508Ile)	RARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435369	NM_002887.4(RARS1):c.1535G>T (p.Arg512Leu)	RARS1	Uncertain significance	criteria provided, single submitter
2435370	NM_002887.4(RARS1):c.847G>A (p.Glu283Lys)	RARS1	Uncertain significance	criteria provided, single submitter
2441849	NM_002887.4(RARS1):c.180+5G>A	RARS1	Uncertain significance	criteria provided, single submitter
2445983	NM_002887.4(RARS1):c.1662_1663delinsTT (p.Met554_Leu555delinsIlePhe)	RARS1	Uncertain significance	criteria provided, single submitter
2576788	NM_002887.4(RARS1):c.227TTA[1] (p.Ile77del)	RARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
423665	NM_002887.4(RARS1):c.668G>A (p.Arg223His)	RARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
RARS1	Definitive	Autosomal recessive	hypomyelinating leukodystrophy 9	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RARS1	Orphanet:438114	RARS-related autosomal recessive hypomyelinating leukodystrophy

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
RARS1	HGNC:9870	ENSG00000113643	P54136	Arginine–tRNA ligase, cytoplasmic	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RARS1	Arginine–tRNA ligase, cytoplasmic	Forms part of a macromolecular complex that catalyzes the attachment of specific amino acids to cognate tRNAs during protein synthesis.

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)
RARS1	Enzyme (other)	yes	6.1.1.19	Arg-tRNA-ligase, aa-tRNA-synth_I_CS, Arg-tRNA-synth_N

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
calcaneal tendon	1
esophagus squamous epithelium	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RARS1	236	ubiquitous	marker	calcaneal tendon, jejunal mucosa, esophagus squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RARS1	4,094

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RARS1	P54136	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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×	0.014	RARS1
tRNA Aminoacylation	1	285.5×	0.014	RARS1
Selenoamino acid metabolism	1	196.9×	0.014	RARS1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.014	RARS1
MITF-M-regulated melanocyte development	1	114.2×	0.018	RARS1
Metabolism of amino acids and derivatives	1	67.6×	0.023	RARS1
Translation	1	62.1×	0.023	RARS1
Developmental Biology	1	14.5×	0.086	RARS1
Metabolism of proteins	1	12.4×	0.086	RARS1
Metabolism	1	11.6×	0.086	RARS1

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
arginyl-tRNA aminoacylation	1	5617.3×	4e-04	RARS1
tRNA aminoacylation for protein translation	1	842.6×	0.001	RARS1

Therapeutics

Drug target analysis

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

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
RARS1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RARS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RARS1	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RARS1	6.1.1.19	arginine-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

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	RARS1

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	RARS1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.