Leukodystrophy, hypomyelinating, 18

Summary

Leukodystrophy, hypomyelinating, 18 (MONDO:0032730) is a disease caused by DEGS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: DEGS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukodystrophy, hypomyelinating, 18
Mondo ID	MONDO:0032730
OMIM	618404
DOID	DOID:0070399
UMLS	C5193078
MedGen	1680067
GARD	0025731
Is cancer (heuristic)	no

Also known as: HLD18

Data availability: 20 ClinVar variants · 5 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, 18

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, 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

20 retrieved; paginated sample, class counts are floors:

5 likely pathogenic, 4 pathogenic/likely pathogenic, 4 uncertain significance, 4 pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172541	NM_003676.4(DEGS1):c.852_855del (p.Tyr283_Tyr284insTer)	DEGS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3770186	Single allele	DEGS1	Pathogenic	criteria provided, single submitter
625852	NM_003676.4(DEGS1):c.764A>G (p.Asn255Ser)	DEGS1	Pathogenic	criteria provided, multiple submitters, no conflicts
626327	NM_003676.4(DEGS1):c.341_342del (p.Leu114fs)	DEGS1	Pathogenic	no assertion criteria provided
626328	NM_003676.4(DEGS1):c.604del (p.Tyr202fs)	DEGS1	Pathogenic	no assertion criteria provided
626329	NM_003676.4(DEGS1):c.337A>G (p.Asn113Asp)	DEGS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
626330	NM_003676.4(DEGS1):c.320G>A (p.Trp107Ter)	DEGS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
805858	NM_003676.4(DEGS1):c.517C>T (p.Arg173Ter)	DEGS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2502429	NM_003676.4(DEGS1):c.826-1G>A	DEGS1	Likely pathogenic	criteria provided, single submitter
2584783	NM_003676.4(DEGS1):c.2T>C (p.Met1Thr)	DEGS1	Likely pathogenic	criteria provided, single submitter
3062080	NM_003676.4(DEGS1):c.775C>T (p.His259Tyr)	DEGS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
626324	NM_003676.4(DEGS1):c.839C>T (p.Ala280Val)	DEGS1	Likely pathogenic	criteria provided, single submitter
805859	NM_003676.4(DEGS1):c.397C>T (p.Arg133Trp)	DEGS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
626325	NM_003676.4(DEGS1):c.395A>G (p.His132Arg)	DEGS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
805856	NM_003676.4(DEGS1):c.110T>C (p.Met37Thr)	DEGS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
805860	NM_003676.4(DEGS1):c.565A>G (p.Asn189Asp)	DEGS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3065976	NM_003676.4(DEGS1):c.383A>T (p.His128Leu)	DEGS1	Uncertain significance	criteria provided, single submitter
3500838	NM_003676.4(DEGS1):c.250A>G (p.Met84Val)	DEGS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779228	NM_003676.4(DEGS1):c.178A>G (p.Ile60Val)	DEGS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
805857	NM_003676.4(DEGS1):c.878G>A (p.Trp293Ter)	DEGS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
DEGS1	Definitive	Autosomal recessive	leukodystrophy, hypomyelinating, 18	5

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
DEGS1	HGNC:13709	ENSG00000143753	O15121	Sphingolipid delta(4)-desaturase DES1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DEGS1	Sphingolipid delta(4)-desaturase DES1	Has sphingolipid-delta-4-desaturase activity.

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)
DEGS1	Enzyme (other)	yes	1.14.19.17	FA_desaturase_dom, DES1/DES2, Sphingolipid_d4-desaturase_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
penis	1
skin of hip	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DEGS1	293	ubiquitous	marker	skin of hip, upper leg skin, penis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DEGS1	1,013

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DEGS1	O15121	96.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Sphingolipid de novo biosynthesis	1	285.5×	0.007	DEGS1
Neutrophil degranulation	1	23.1×	0.043	DEGS1

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
myelin maintenance	1	2808.7×	0.002	DEGS1
unsaturated fatty acid biosynthetic process	1	648.1×	0.003	DEGS1
glycosphingolipid biosynthetic process	1	601.9×	0.003	DEGS1
ceramide biosynthetic process	1	421.3×	0.003	DEGS1
sphingolipid biosynthetic process	1	358.6×	0.003	DEGS1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · 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
DEGS1	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FENRETINIDE	3	DEGS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DEGS1	17	Binding:15, ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DEGS1	1.14.19.17	sphingolipid 4-desaturase

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)
FENRETINIDE	3	DEGS1

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	DEGS1
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.