Gaze palsy, familial horizontal, with progressive scoliosis 1

Summary

Gaze palsy, familial horizontal, with progressive scoliosis 1 (MONDO:0020790) is a disease caused by ROBO3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ROBO3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 150

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	gaze palsy, familial horizontal, with progressive scoliosis 1
Mondo ID	MONDO:0020790
OMIM	607313
UMLS	C4551964
MedGen	1647423
GARD	0025251
Is cancer (heuristic)	no

Also known as: gaze palsy, familial horizontal, with progressive scoliosis 1 · gaze palsy, familial horizontal, with progressive scoliosis, 1 · HGPPS · HGPPS1

Data availability: 150 ClinVar variants · 4 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 1

Related subtypes (1): gaze palsy, familial horizontal, with progressive scoliosis, 2

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

150 retrieved; paginated sample, class counts are floors:

63 uncertain significance, 22 benign, 22 likely pathogenic, 18 conflicting classifications of pathogenicity, 12 pathogenic, 8 likely benign, 4 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4293886	NM_022370.4(ROBO3):c.2562_2566delinsGCA (p.Val855fs)	LOC124625862	Pathogenic	criteria provided, single submitter
1704392	NM_022370.4(ROBO3):c.2770_2779+21del	ROBO3	Pathogenic	criteria provided, multiple submitters, no conflicts
1804990	NM_022370.4(ROBO3):c.571del (p.Arg191fs)	ROBO3	Pathogenic	criteria provided, single submitter
2173	NM_022370.4(ROBO3):c.3325dup (p.Glu1109fs)	ROBO3	Pathogenic	no assertion criteria provided
2176	NM_022370.4(ROBO3):c.1366G>T (p.Gly456Ter)	ROBO3	Pathogenic	no assertion criteria provided
2178	NM_022370.4(ROBO3):c.2315dup (p.Gln773fs)	ROBO3	Pathogenic	no assertion criteria provided
2181	NM_022370.4(ROBO3):c.2073+1G>A	ROBO3	Pathogenic	no assertion criteria provided
2182	NM_022370.4(ROBO3):c.1844_1845del (p.Thr615fs)	ROBO3	Pathogenic	no assertion criteria provided
2183	NM_022370.4(ROBO3):c.1886_1887del (p.Val629fs)	ROBO3	Pathogenic	no assertion criteria provided
2185	NM_022370.4(ROBO3):c.2317C>T (p.Gln773Ter)	ROBO3	Pathogenic	no assertion criteria provided
3896072	NM_022370.4(ROBO3):c.799C>T (p.Gln267Ter)	ROBO3	Pathogenic	criteria provided, single submitter
632150	NM_022370.4(ROBO3):c.571dup (p.Arg191fs)	ROBO3	Pathogenic	criteria provided, multiple submitters, no conflicts
974850	NM_022370.4(ROBO3):c.767-1G>A	ROBO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3906992	NM_022370.4(ROBO3):c.2697_2710dup (p.Leu904fs)	LOC130007006	Likely pathogenic	criteria provided, single submitter
996103	NM_022370.4(ROBO3):c.2663T>C (p.Leu888Pro)	LOC130007006	Likely pathogenic	criteria provided, single submitter
2172	NM_022370.4(ROBO3):c.1082G>A (p.Gly361Glu)	ROBO3	Likely pathogenic	criteria provided, single submitter
2174	NM_022370.4(ROBO3):c.2108G>C (p.Arg703Pro)	ROBO3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2175	NM_022370.4(ROBO3):c.2113T>C (p.Ser705Pro)	ROBO3	Likely pathogenic	criteria provided, single submitter
2177	NM_022370.4(ROBO3):c.955G>A (p.Glu319Lys)	ROBO3	Likely pathogenic	criteria provided, single submitter
2179	NM_022370.4(ROBO3):c.14T>C (p.Leu5Pro)	ROBO3	Likely pathogenic	criteria provided, single submitter
2180	NM_022370.4(ROBO3):c.196A>C (p.Ile66Leu)	ROBO3	Likely pathogenic	criteria provided, single submitter
2184	NM_022370.4(ROBO3):c.733C>T (p.Arg245Trp)	ROBO3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2585490	NM_022370.4(ROBO3):c.3493C>T (p.Gln1165Ter)	ROBO3	Likely pathogenic	criteria provided, single submitter
3064172	NM_022370.4(ROBO3):c.3937C>T (p.Gln1313Ter)	ROBO3	Likely pathogenic	criteria provided, single submitter
3362580	NM_022370.4(ROBO3):c.403_404del (p.Arg135fs)	ROBO3	Likely pathogenic	criteria provided, single submitter
974849	NM_022370.4(ROBO3):c.3412del (p.Arg1138fs)	ROBO3	Likely pathogenic	criteria provided, single submitter
996102	NM_022370.4(ROBO3):c.2312C>T (p.Pro771Leu)	ROBO3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
996105	NM_022370.4(ROBO3):c.1433C>T (p.Pro478Leu)	ROBO3	Likely pathogenic	criteria provided, single submitter
996106	NM_022370.4(ROBO3):c.1450T>C (p.Trp484Arg)	ROBO3	Likely pathogenic	criteria provided, single submitter
996107	NM_022370.4(ROBO3):c.1726T>C (p.Trp576Arg)	ROBO3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ROBO3	Definitive	Autosomal recessive	gaze palsy, familial horizontal, with progressive scoliosis 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ROBO3	Orphanet:2744	Horizontal gaze palsy with progressive scoliosis

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
ROBO3	HGNC:13433	ENSG00000154134	Q96MS0	Roundabout homolog 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ROBO3	Roundabout homolog 3	Receptor involved in axon guidance during development.

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)
ROBO3	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
left ovary	1
right ovary	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ROBO3	238	ubiquitous	marker	right uterine tube, left ovary, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ROBO3	1,382

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ROBO3	Q96MS0	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
ROBO receptors bind AKAP5	1	1268.9×	0.002	ROBO3
Regulation of commissural axon pathfinding by SLIT and ROBO	1	951.7×	0.002	ROBO3
Regulation of expression of SLITs and ROBOs	1	69.2×	0.014	ROBO3

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
positive regulation of axon guidance	1	8426.0×	9e-04	ROBO3
negative regulation of negative chemotaxis	1	5617.3×	9e-04	ROBO3
tube development	1	4213.0×	9e-04	ROBO3
axon midline choice point recognition	1	3370.4×	9e-04	ROBO3
dendrite self-avoidance	1	1053.2×	0.002	ROBO3
commissural neuron axon guidance	1	991.3×	0.002	ROBO3
positive regulation of axonogenesis	1	581.1×	0.003	ROBO3
homophilic cell-cell adhesion	1	140.4×	0.009	ROBO3
chemotaxis	1	135.9×	0.009	ROBO3
neuron migration	1	133.8×	0.009	ROBO3
axon guidance	1	90.6×	0.012	ROBO3
brain development	1	79.5×	0.013	ROBO3

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
ROBO3	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	ROBO3
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)
ROBO3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.