Hypomyelinating leukodystrophy 5

Summary

Hypomyelinating leukodystrophy 5 (MONDO:0012514) is a disease caused by HYCC1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HYCC1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 300
• Phenotypes (HPO): 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000519	Developmental cataract	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001317	Abnormal cerebellum morphology	Very frequent (80-99%)
HP:0002342	Intellectual disability, moderate	Very frequent (80-99%)
HP:0006808	Cerebral hypomyelination	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelinating leukodystrophy 5
Mondo ID	MONDO:0012514
MeSH	C567166
OMIM	610532
Orphanet	85163
DOID	DOID:0060793
SNOMED CT	702379005
UMLS	C1864663
MedGen	501134
GARD	0011980
Is cancer (heuristic)	no

Also known as: FAM126A leukodystrophy · HLD5 · hypomyelinating leukodystrophy type 5 · hypomyelination - congenital cataract · hypomyelination and congenital cataract · hypomyelination-congenital cataract syndrome · leukodystrophy caused by mutation in FAM126A · leukodystrophy, hypomyelinating, 5 · leukodystrophy, hypomyelinating, type 5

Data availability: 300 ClinVar variants · 4 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 5

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, 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, 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

300 retrieved; paginated sample, class counts are floors:

134 uncertain significance, 97 likely benign, 27 benign, 14 conflicting classifications of pathogenicity, 9 likely pathogenic, 7 pathogenic, 6 benign/likely benign, 5 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424085	NC_000007.13:g.(?20994491)(23030730_?)del	CDCA7L	Pathogenic	criteria provided, single submitter
1199229	NM_032581.4(HYCC1):c.150_151dup (p.Glu51fs)	HYCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1214	NM_032581.4(HYCC1):c.51+1G>A	HYCC1	Pathogenic	criteria provided, single submitter
1215	NM_032581.4(HYCC1):c.414+1G>T	HYCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1216	NM_032581.4(HYCC1):c.158T>C (p.Leu53Pro)	HYCC1	Pathogenic	no assertion criteria provided
1333193	NM_032581.4(HYCC1):c.722T>G (p.Leu241Ter)	HYCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457726	NM_032581.4(HYCC1):c.649C>T (p.Arg217Ter)	HYCC1	Pathogenic	criteria provided, single submitter
1458225	NM_032581.4(HYCC1):c.414+1G>A	HYCC1	Pathogenic	criteria provided, single submitter
21725	NM_032581.4(HYCC1):c.627-439_831+348del	HYCC1	Pathogenic	no assertion criteria provided
2501025	NM_032581.4(HYCC1):c.639del (p.Cys213fs)	HYCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3632712	NM_032581.4(HYCC1):c.781del (p.Asp261fs)	HYCC1	Pathogenic	criteria provided, single submitter
450984	NM_032581.4(HYCC1):c.125dup (p.Tyr42Ter)	HYCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1506613	NM_032581.4(HYCC1):c.831+1G>T	HYCC1	Likely pathogenic	criteria provided, single submitter
1679236	NM_032581.4(HYCC1):c.832-2A>T	HYCC1	Likely pathogenic	criteria provided, single submitter
2116835	NM_032581.4(HYCC1):c.154-1G>T	HYCC1	Likely pathogenic	criteria provided, single submitter
2503877	NM_032581.4(HYCC1):c.349C>T (p.Gln117Ter)	HYCC1	Likely pathogenic	criteria provided, single submitter
3064074	NM_032581.4(HYCC1):c.145C>T (p.Gln49Ter)	HYCC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293621	NM_032581.4(HYCC1):c.1176del (p.Glu393fs)	HYCC1	Likely pathogenic	criteria provided, single submitter
430054	NM_032581.4(HYCC1):c.229C>T (p.Gln77Ter)	HYCC1	Likely pathogenic	criteria provided, single submitter
635049	NM_032581.4(HYCC1):c.100_101del (p.Lys34fs)	HYCC1	Likely pathogenic	criteria provided, single submitter
4278477	NM_001282717.2(STAG3):c.2291del (p.Asp764fs)	STAG3	Likely pathogenic	criteria provided, single submitter
333435	NM_032977.4(CASP10):c.1216A>T (p.Ile406Leu)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1584289	NM_032581.4(HYCC1):c.52-9T>A	HYCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3336789	NM_032581.4(HYCC1):c.169T>C (p.Cys57Arg)	HYCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359769	NM_032581.4(HYCC1):c.1515A>G (p.Gln505=)	HYCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359771	NM_032581.4(HYCC1):c.1220G>A (p.Arg407Gln)	HYCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359783	NM_032581.4(HYCC1):c.281A>G (p.Asn94Ser)	HYCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
430052	NM_032581.4(HYCC1):c.1492A>G (p.Thr498Ala)	HYCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
701831	NM_032581.4(HYCC1):c.191A>G (p.Tyr64Cys)	HYCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
706630	NM_032581.4(HYCC1):c.972T>G (p.Gly324=)	HYCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
HYCC1	Definitive	Autosomal recessive	hypomyelinating leukodystrophy 5	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HYCC1	Orphanet:85163	Hypomyelination-congenital cataract syndrome
STAG3	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
CASP10	Orphanet:3261	Autoimmune lymphoproliferative syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HYCC1	HGNC:24587	ENSG00000122591	Q9BYI3	Hyccin	gencc,clinvar
STAG3	HGNC:11356	ENSG00000066923	Q9UJ98	Cohesin subunit SA-3	clinvar
FEZF2	HGNC:13506	ENSG00000153266	Q8TBJ5	Fez family zinc finger protein 2	clinvar
CASP10	HGNC:1500	ENSG00000003400	Q92851	Caspase-10	clinvar
CDCA7L	HGNC:30777	ENSG00000164649	Q96GN5	Cell division cycle-associated 7-like protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HYCC1	Hyccin	Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane.
STAG3	Cohesin subunit SA-3	Meiosis specific component of cohesin complex.
FEZF2	Fez family zinc finger protein 2	Transcription repressor.
CASP10	Caspase-10	Involved in the activation cascade of caspases responsible for apoptosis execution.
CDCA7L	Cell division cycle-associated 7-like protein	Plays a role in transcriptional regulation as a repressor that inhibits monoamine oxidase A (MAOA) activity and gene expression by binding to the promoter.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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
Transcription factor	2	3.3×	0.343
Enzyme (other)	1	2.4×	0.530
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HYCC1	Other/Unknown	no		Hyccin
STAG3	Other/Unknown	no		STAG, ARM-type_fold, SCD
FEZF2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
CASP10	Enzyme (other)	yes	3.4.22.63	Pept_C14_p20, DED_dom, Pept_C14_p10
CDCA7L	Transcription factor	no		Znf-4CXXC_R1, CDCA7/CDA7L

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
calcaneal tendon	1
endothelial cell	1
sural nerve	1
left testis	1
oocyte	1
right testis	1
cortical plate	1
ganglionic eminence	1
colonic epithelium	1
granulocyte	1
monocyte	1
germinal epithelium of ovary	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HYCC1	250	ubiquitous	marker	calcaneal tendon, endothelial cell, sural nerve
STAG3	185	broad	marker	oocyte, right testis, left testis
FEZF2	90	tissue_specific	marker	cortical plate, ventricular zone, ganglionic eminence
CASP10	206	ubiquitous	marker	colonic epithelium, granulocyte, monocyte
CDCA7L	239	ubiquitous	marker	germinal epithelium of ovary, primordial germ cell in gonad, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FEZF2	1,419
CDCA7L	1,413
CASP10	1,242
STAG3	1,232
HYCC1	700

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HYCC1	Q9BYI3	5
CDCA7L	Q96GN5	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STAG3	Q9UJ98	78.46
CASP10	Q92851	69.54
FEZF2	Q8TBJ5	55.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 5 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
FasL/ CD95L signaling	1	1142.0×	0.010	CASP10
TRAIL signaling	1	713.8×	0.010	CASP10
TP53 Regulates Transcription of Caspase Activators and Caspases	1	475.8×	0.010	CASP10
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	439.2×	0.010	CASP10
TP53 Regulates Transcription of Cell Death Genes	1	271.9×	0.013	CASP10
Meiosis	1	142.8×	0.020	STAG3
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	126.9×	0.020	CASP10
Reproduction	1	95.2×	0.024	STAG3
Meiotic synapsis	1	70.5×	0.026	STAG3
Death Receptor Signaling	1	69.6×	0.026	CASP10
Transcriptional Regulation by TP53	1	31.0×	0.052	CASP10
Cell Cycle	1	18.0×	0.082	STAG3
Innate Immune System	1	12.8×	0.107	CASP10
RNA Polymerase II Transcription	1	11.3×	0.112	CASP10
Gene expression (Transcription)	1	8.9×	0.131	CASP10
Generic Transcription Pathway	1	7.5×	0.144	CASP10
Immune System	1	6.5×	0.157	CASP10
Signal Transduction	1	5.1×	0.187	CASP10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
forebrain anterior/posterior pattern specification	1	842.6×	0.010	FEZF2
establishment of meiotic sister chromatid cohesion	1	842.6×	0.010	STAG3
cerebral cortex GABAergic interneuron migration	1	561.7×	0.010	FEZF2
commitment of neuronal cell to specific neuron type in forebrain	1	561.7×	0.010	FEZF2
cell dedifferentiation	1	561.7×	0.010	FEZF2
regulation of axon guidance	1	481.5×	0.010	FEZF2
neuron fate determination	1	421.3×	0.010	FEZF2
axonal fasciculation	1	187.2×	0.019	FEZF2
positive regulation of execution phase of apoptosis	1	168.5×	0.019	CASP10
sister chromatid cohesion	1	153.2×	0.019	STAG3
synaptonemal complex assembly	1	129.6×	0.019	STAG3
dentate gyrus development	1	124.8×	0.019	FEZF2
phosphatidylinositol phosphate biosynthetic process	1	96.3×	0.023	HYCC1
regulation of neurogenesis	1	80.2×	0.025	FEZF2
dendrite development	1	78.4×	0.025	FEZF2
positive regulation of neuron apoptotic process	1	54.4×	0.031	CASP10
negative regulation of neuron differentiation	1	54.4×	0.031	FEZF2
myelination	1	50.3×	0.032	HYCC1
positive regulation of neuron differentiation	1	39.6×	0.038	FEZF2
locomotory behavior	1	35.9×	0.040	FEZF2
protein maturation	1	32.7×	0.042	CASP10
protein localization to plasma membrane	1	21.7×	0.060	HYCC1
regulation of gene expression	1	16.7×	0.074	FEZF2
positive regulation of canonical NF-kappaB signal transduction	1	14.5×	0.081	CASP10
negative regulation of cell population proliferation	1	8.4×	0.131	FEZF2
proteolysis	1	6.8×	0.150	CASP10
positive regulation of cell population proliferation	1	6.7×	0.150	CDCA7L
regulation of DNA-templated transcription	1	6.3×	0.154	CDCA7L
apoptotic process	1	5.7×	0.162	CASP10

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HYCC1	0	0
STAG3	0	0
FEZF2	0	0
CASP10	0	0
CDCA7L	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
CASP10	22	Binding:21, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CASP10	3.4.22.63	caspase-10

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	0
D	Druggable family + AlphaFold only, no drug	1	CASP10
E	Difficult family or no structure, no drug	4	HYCC1, STAG3, FEZF2, CDCA7L

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HYCC1	0	—
STAG3	0	—
FEZF2	0	—
CASP10	22	—
CDCA7L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.