Hypomyelinating leukodystrophy 2

Summary

Hypomyelinating leukodystrophy 2 (MONDO:0012125) is a disease caused by GJC2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: GJC2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 84

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelinating leukodystrophy 2
Mondo ID	MONDO:0012125
MeSH	C563855
OMIM	608804
Orphanet	280282
DOID	DOID:0060787
UMLS	C1837355
MedGen	325157
GARD	0017293
Is cancer (heuristic)	no

Also known as: GJC2 leukodystrophy · HLD2 · hypomyelinating leukodystrophy type 2 · leukodystrophy caused by mutation in GJC2 · leukodystrophy, hypomyelinating, 2 · leukodystrophy, hypomyelinating, type 2 · Pelizaeus-Merzbacher-like disease due to GJC2 mutation · PMLD1

Data availability: 84 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 › Pelizaeus-Merzbacher-like disease › hypomyelinating leukodystrophy 2

Related subtypes (2): hypomyelinating leukodystrophy 3, hypomyelinating leukodystrophy 4

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

84 retrieved; paginated sample, class counts are floors:

27 likely pathogenic, 21 uncertain significance, 17 pathogenic, 11 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
235616	NM_000159.4(GCDH):c.1156C>T (p.Arg386Ter)	GCDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1027507	NM_020435.4(GJC2):c.219_220del (p.Leu74fs)	GJC2	Pathogenic	criteria provided, single submitter
139577	NC_000001.11:g.228149857A>G	GJC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1525995	NM_020435.4(GJC2):c.472_481dup (p.Ala161fs)	GJC2	Pathogenic	criteria provided, single submitter
2071	NM_020435.4(GJC2):c.857T>C (p.Met286Thr)	GJC2	Pathogenic	criteria provided, single submitter
2073	NM_020435.4(GJC2):c.989del (p.Pro330fs)	GJC2	Pathogenic	no assertion criteria provided
2074	NM_020435.4(GJC2):c.718C>T (p.Arg240Ter)	GJC2	Pathogenic	criteria provided, single submitter
2075	NM_020435.4(GJC2):c.814T>G (p.Tyr272Asp)	GJC2	Pathogenic	no assertion criteria provided
2076	NM_020435.4(GJC2):c.914_947del (p.Pro305fs)	GJC2	Pathogenic	criteria provided, single submitter
2077	NM_020435.4(GJC2):c.695_696insG (p.Tyr232Ter)	GJC2	Pathogenic	no assertion criteria provided
235629	NM_020435.4(GJC2):c.17G>A (p.Trp6Ter)	GJC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30759	NM_020435.4(GJC2):c.-167A>G	GJC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3336782	NM_020435.4(GJC2):c.790A>T (p.Lys264Ter)	GJC2	Pathogenic	criteria provided, single submitter
3338029	NM_020435.4(GJC2):c.282C>G (p.Tyr94Ter)	GJC2	Pathogenic	criteria provided, single submitter
3340090	NM_020435.4(GJC2):c.404G>A (p.Trp135Ter)	GJC2	Pathogenic	criteria provided, single submitter
3896190	NM_020435.4(GJC2):c.523G>T (p.Glu175Ter)	GJC2	Pathogenic	criteria provided, single submitter
426207	NM_020435.4(GJC2):c.970_971dup (p.Ala325fs)	GJC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4848031	NM_020435.4(GJC2):c.914_947dup (p.Pro317fs)	GJC2	Pathogenic	criteria provided, single submitter
60683	NM_020435.4(GJC2):c.787G>A (p.Glu263Lys)	GJC2	Pathogenic	no assertion criteria provided
656694	NM_020435.4(GJC2):c.1134_1144del (p.Ala379fs)	GJC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
817577	NM_020435.4(GJC2):c.23_24delinsAA (p.Phe8Ter)	GJC2	Pathogenic	criteria provided, multiple submitters, no conflicts
873005	NM_020435.4(GJC2):c.575dup (p.Thr195fs)	GJC2	Pathogenic	criteria provided, single submitter
279894	NM_004782.4(SNAP29):c.2T>C (p.Met1Thr)	SNAP29	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279932	NM_004782.4(SNAP29):c.354dup (p.Leu119fs)	SNAP29	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027508	NM_020435.4(GJC2):c.254T>C (p.Val85Ala)	GJC2	Likely pathogenic	criteria provided, single submitter
1180631	NM_020435.4(GJC2):c.760G>A (p.Val254Met)	GJC2	Likely pathogenic	criteria provided, single submitter
1339504	NM_020435.4(GJC2):c.371_392dup (p.His132fs)	GJC2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339505	NM_020435.4(GJC2):c.755A>G (p.His252Arg)	GJC2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2072	NM_020435.4(GJC2):c.268C>T (p.Pro90Ser)	GJC2	Likely pathogenic	criteria provided, single submitter
266108	NM_020435.4(GJC2):c.78del (p.Trp27fs)	GJC2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 5 · 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
GJC2	Definitive	Autosomal recessive	hypomyelinating leukodystrophy 2	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJC2	Orphanet:280282	Pelizaeus-Merzbacher-like disease due to GJC2 mutation
GJC2	Orphanet:320401	Autosomal recessive spastic paraplegia type 44
GJC2	Orphanet:568051	GJC2-related late-onset primary lymphedema
SNAP29	Orphanet:66631	CEDNIK syndrome
GCDH	Orphanet:25	Glutaryl-CoA dehydrogenase deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJC2	HGNC:17494	ENSG00000198835	Q5T442	Gap junction gamma-2 protein	gencc,clinvar
SNAP29	HGNC:11133	ENSG00000099940	O95721	Synaptosomal-associated protein 29	clinvar
GCDH	HGNC:4189	ENSG00000105607	Q92947	Glutaryl-CoA dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJC2	Gap junction gamma-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
SNAP29	Synaptosomal-associated protein 29	SNAREs, soluble N-ethylmaleimide-sensitive factor-attachment protein receptors, are essential proteins for fusion of cellular membranes.
GCDH	Glutaryl-CoA dehydrogenase, mitochondrial	Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJC2	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
SNAP29	Other/Unknown	no		T_SNARE_dom
GCDH	Enzyme (other)	yes	1.3.8.6	Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
inferior vagus X ganglion	1
spinal cord	1
left testis	1
primordial germ cell in gonad	1
right testis	1
apex of heart	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJC2	181	tissue_specific	yes	C1 segment of cervical spinal cord, spinal cord, inferior vagus X ganglion
SNAP29	290	ubiquitous	marker	left testis, right testis, primordial germ cell in gonad
GCDH	259	ubiquitous	marker	right lobe of liver, liver, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SNAP29	2,703
GCDH	2,573
GJC2	638

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCDH	Q92947	4
SNAP29	O95721	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJC2	Q5T442	68.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Lysine catabolism	1	380.7×	0.024	GCDH
Gap junction assembly	1	97.6×	0.035	GJC2
Intra-Golgi traffic	1	86.5×	0.035	SNAP29
Intra-Golgi and retrograde Golgi-to-ER traffic	1	34.9×	0.064	SNAP29
Membrane Trafficking	1	12.4×	0.126	SNAP29
Vesicle-mediated transport	1	11.6×	0.126	SNAP29
Innate Immune System	1	8.5×	0.140	SNAP29
Neutrophil degranulation	1	7.7×	0.140	SNAP29
Immune System	1	4.3×	0.214	SNAP29

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete L-tryptophan metabolic process	1	1872.4×	0.004	GCDH
cell communication by electrical coupling	1	1404.3×	0.004	GJC2
autophagosome membrane docking	1	802.5×	0.004	SNAP29
fatty-acyl-CoA biosynthetic process	1	624.1×	0.004	GCDH
obsolete vesicle targeting	1	561.7×	0.004	SNAP29
synaptic vesicle fusion to presynaptic active zone membrane	1	561.7×	0.004	SNAP29
fatty acid beta-oxidation using acyl-CoA dehydrogenase	1	468.1×	0.005	GCDH
synaptic vesicle priming	1	267.5×	0.007	SNAP29
membrane fusion	1	208.1×	0.008	SNAP29
autophagosome maturation	1	117.0×	0.013	SNAP29
response to toxic substance	1	70.2×	0.019	GJC2
exocytosis	1	50.6×	0.025	SNAP29
cilium assembly	1	24.5×	0.046	SNAP29
cell-cell signaling	1	23.2×	0.046	GJC2
protein transport	1	14.6×	0.067	SNAP29

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GCDH	BALSALAZIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCDH	1	4
GJC2	0	0
SNAP29	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BALSALAZIDE	4	GCDH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GCDH	15	Binding:14, ADMET:1
SNAP29	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCDH	1.3.8.6	glutaryl-CoA dehydrogenase (ETF)

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
BALSALAZIDE	4	GCDH

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GCDH
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	GJC2, SNAP29

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)
GJC2	0	—
SNAP29	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.