Gaze palsy, familial horizontal, with progressive scoliosis, 2

Summary

Gaze palsy, familial horizontal, with progressive scoliosis, 2 (MONDO:0054602) is a disease caused by DCC (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: DCC (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	gaze palsy, familial horizontal, with progressive scoliosis, 2
Mondo ID	MONDO:0054602
OMIM	617542
UMLS	C4479640
MedGen	1393733
GARD	0016234
Is cancer (heuristic)	no

Also known as: gaze palsy, familial horizontal, with progressive scoliosis, 2 · HGPPS2

Data availability: 16 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › horizontal gaze palsy with progressive scoliosis › gaze palsy, familial horizontal, with progressive scoliosis, 2

Related subtypes (1): gaze palsy, familial horizontal, with progressive scoliosis 1

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

16 retrieved; paginated sample, class counts are floors:

7 benign, 3 pathogenic, 3 benign/likely benign, 2 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1802587	NM_005215.4(DCC):c.[4009C>T;4210G>A]		Pathogenic	criteria provided, single submitter
446724	NM_005215.4(DCC):c.788_794del (p.Val263fs)	DCC	Pathogenic	criteria provided, single submitter
446759	NM_005215.4(DCC):c.31_91+7622del	DCC	Pathogenic	no assertion criteria provided
719574	NM_005215.4(DCC):c.1256A>G (p.Lys419Arg)	DCC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
446760	NM_005215.4(DCC):c.2071C>A (p.Gln691Lys)	DCC	Uncertain significance	no assertion criteria provided
930503	NM_005215.4(DCC):c.769G>A (p.Ala257Thr)	DCC	Uncertain significance	criteria provided, single submitter
1255454	NM_005215.4(DCC):c.67T>C (p.Phe23Leu)	DCC	Benign	criteria provided, multiple submitters, no conflicts
1255455	NM_005215.4(DCC):c.354G>A (p.Glu118=)	DCC	Benign	criteria provided, multiple submitters, no conflicts
1255456	NM_005215.4(DCC):c.2053+13A>G	DCC	Benign	criteria provided, multiple submitters, no conflicts
1255457	NM_005215.4(DCC):c.3108T>C (p.Pro1036=)	DCC	Benign	criteria provided, multiple submitters, no conflicts
1255458	NM_005215.4(DCC):c.3130+10A>G	DCC	Benign	criteria provided, multiple submitters, no conflicts
709096	NM_005215.4(DCC):c.91+7G>A	DCC	Benign	criteria provided, multiple submitters, no conflicts
714873	NM_005215.4(DCC):c.2158C>T (p.Leu720=)	DCC	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
773345	NM_005215.4(DCC):c.1062C>T (p.Val354=)	DCC	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
778536	NM_005215.4(DCC):c.2053+9T>C	DCC	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
803493	NM_005215.4(DCC):c.601C>G (p.Arg201Gly)	DCC	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
DCC	Strong	Autosomal recessive	gaze palsy, familial horizontal, with progressive scoliosis, 2	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DCC	Orphanet:238722	Familial congenital mirror movements
DCC	Orphanet:2744	Horizontal gaze palsy with progressive scoliosis
DCC	Orphanet:478	Kallmann syndrome

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
DCC	HGNC:2701	ENSG00000187323	P43146	Netrin receptor DCC	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DCC	Netrin receptor DCC	Receptor for netrin required for axon guidance.

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DCC	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

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
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DCC	154	broad	marker	cortical plate, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DCC	1,333

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DCC	P43146	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
DSCAM interactions	1	2284.0×	0.001	DCC
Netrin mediated repulsion signals	1	1268.9×	0.001	DCC
Caspase activation via Dependence Receptors in the absence of ligand	1	1142.0×	0.001	DCC
Role of second messengers in netrin-1 signaling	1	1038.2×	0.001	DCC
Regulation of commissural axon pathfinding by SLIT and ROBO	1	951.7×	0.001	DCC
DCC mediated attractive signaling	1	713.8×	0.002	DCC
Netrin-1 signaling	1	439.2×	0.002	DCC

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
spinal cord ventral commissure morphogenesis	1	5617.3×	0.001	DCC
dorsal/ventral axon guidance	1	4213.0×	0.001	DCC
anterior/posterior axon guidance	1	2808.7×	0.001	DCC
negative regulation of dendrite development	1	2106.5×	0.001	DCC
negative regulation of collateral sprouting	1	1532.0×	0.002	DCC
postsynaptic modulation of chemical synaptic transmission	1	674.1×	0.003	DCC
negative regulation of neuron projection development	1	237.3×	0.007	DCC
axonogenesis	1	160.5×	0.009	DCC
neuron migration	1	133.8×	0.010	DCC
cell-cell adhesion	1	101.5×	0.012	DCC
axon guidance	1	90.6×	0.012	DCC
apoptotic process	1	28.7×	0.035	DCC

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DCC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	DCC
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)
DCC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.