Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Summary

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (MONDO:0008641) is a disease caused by TREX1 (GenCC Strong), with 3 cohort genes and 1 clinical trial. Top therapeutic interventions include aclarubicin.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: TREX1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 546
• Phenotypes (HPO): 50
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0002500	Abnormal cerebral white matter morphology	Very frequent (80-99%)
HP:0008046	Abnormal retinal vascular morphology	Very frequent (80-99%)
HP:0030880	Raynaud phenomenon	Very frequent (80-99%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000096	Glomerulosclerosis	Frequent (30-79%)
HP:0000112	Nephropathy	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0001895	Normochromic anemia	Frequent (30-79%)
HP:0001897	Normocytic anemia	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Frequent (30-79%)
HP:0003259	Elevated circulating creatinine concentration	Frequent (30-79%)
HP:0006707	Abnormality of the hepatic vasculature	Frequent (30-79%)
HP:0008223	Compensated hypothyroidism	Frequent (30-79%)
HP:0011954	Nodular regenerative hyperplasia of liver	Frequent (30-79%)
HP:0030948	Elevated gamma-glutamyltransferase level	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0001009	Telangiectasia	Occasional (5-29%)
HP:0001123	Visual field defect	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0002077	Migraine with aura	Occasional (5-29%)
HP:0002083	Migraine without aura	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0002197	Generalized-onset seizure	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002344	Progressive neurologic deterioration	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002381	Aphasia	Occasional (5-29%)
HP:0002514	Cerebral calcification	Occasional (5-29%)
HP:0011163	Somatosensory auras	Occasional (5-29%)
HP:0012377	Hemianopia	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Occasional (5-29%)
HP:0030666	Retinal neovascularization	Occasional (5-29%)
HP:0031606	Retinal cotton wool spot	Occasional (5-29%)
HP:0040049	Macular edema	Occasional (5-29%)
HP:0040328	Focal hyperintensity of cerebral white matter on MRI	Occasional (5-29%)
HP:0040331	Focal hypointensity of cerebral white matter on MRI	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)
HP:0000988	Skin rash	Very rare (<1-4%)
HP:0005743	Avascular necrosis of the capital femoral epiphysis	Very rare (<1-4%)
HP:0200030	Punctate vasculitis skin lesions	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations
Mondo ID	MONDO:0008641
MeSH	C566007
OMIM	192315
Orphanet	247691
DOID	DOID:0111567
ICD-11	554838792
SNOMED CT	720854004, 721141004
UMLS	C1860518
MedGen	348124
GARD	0001217
NORD	1910
Is cancer (heuristic)	no

Also known as: ADRVCL · autosomal dominant retinal vasculopathy with cerebral leukodystrophy · cerebroretinal vasculopathy · cerebroretinal vasculopathy, hereditary · CRV · grand Kaine fulling syndrome · grand-Kaine-fulling syndrome · hereditary vascular retinopathy · HVR · retinal vasculopathy and cerebral leukoencephalopathy · retinal vasculopathy with cerebral leukodystrophy · retinopathy, vascular, with cerebral and renal involvement and Raynaud and migraine phenomena · RVCL · RVCL-S · vasculopathy, retinal, with cerebral leukodystrophy · vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations

Data availability: 546 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal vascular disorder › retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Related subtypes (11): retinal microaneurysm, retinal vascular occlusion, retinal hemangioblastoma, retinal telangiectasia, diabetic retinopathy, retinal vasculitis, familial retinal arterial macroaneurysm, vasoproliferative tumor of retina, exudative vitreoretinopathy, arteriosclerotic retinopathy, perifoveal exudative vascular anomalous complex

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

546 retrieved; paginated sample, class counts are floors:

324 uncertain significance, 134 likely benign, 31 pathogenic, 26 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 7 likely pathogenic, 5 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068732	NC_000003.11:g.(?48507870)(50340407_?)del	AMIGO3	Pathogenic	criteria provided, single submitter
1069131	NM_033629.6(TREX1):c.403C>T (p.Gln135Ter)	ATRIP	Pathogenic	criteria provided, single submitter
1069943	NM_033629.6(TREX1):c.123_125dup (p.Cys42Ter)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1216160	NM_033629.6(TREX1):c.144del (p.Thr49fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126386	NM_033629.6(TREX1):c.366_368dup (p.Ala123_His124insAla)	ATRIP	Pathogenic	criteria provided, single submitter
126389	NM_033629.6(TREX1):c.500del (p.Ser167fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126390	NM_033629.6(TREX1):c.58dup (p.Glu20fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333993	NM_033629.6(TREX1):c.621_622del (p.Ile207fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1430592	NM_033629.6(TREX1):c.153_166del (p.Gln51fs)	ATRIP	Pathogenic	criteria provided, single submitter
1433355	NM_033629.6(TREX1):c.296_299dup (p.Phe100fs)	ATRIP	Pathogenic	criteria provided, single submitter
1455316	NM_033629.6(TREX1):c.5del (p.Gly2fs)	ATRIP	Pathogenic	criteria provided, single submitter
1690729	NM_033629.6(TREX1):c.150_151del (p.Gln51fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2127740	NM_033629.6(TREX1):c.18dup (p.Pro7fs)	ATRIP	Pathogenic	criteria provided, single submitter
225499	NM_033629.6(TREX1):c.294dup (p.Cys99fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
282766	NM_033629.6(TREX1):c.144dup (p.Thr49fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
282767	NM_033629.6(TREX1):c.152_153del (p.Gln51fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2930302	NM_033629.6(TREX1):c.226_233dup (p.Ser78fs)	ATRIP	Pathogenic	criteria provided, single submitter
2936844	NM_033629.6(TREX1):c.349C>T (p.Gln117Ter)	ATRIP	Pathogenic	criteria provided, single submitter
2936991	NM_033629.6(TREX1):c.522_523delinsTT (p.Arg174_Lys175delinsSerTer)	ATRIP	Pathogenic	criteria provided, single submitter
2942588	NM_033629.6(TREX1):c.205_206del (p.Leu69fs)	ATRIP	Pathogenic	criteria provided, single submitter
2942595	NM_033629.6(TREX1):c.371_381del (p.His124fs)	ATRIP	Pathogenic	criteria provided, single submitter
2944466	NM_033629.6(TREX1):c.76_80dup (p.Gln28fs)	ATRIP	Pathogenic	criteria provided, single submitter
2945896	NM_033629.6(TREX1):c.69dup (p.Pro25fs)	ATRIP	Pathogenic	criteria provided, single submitter
2947312	NM_033629.6(TREX1):c.565C>T (p.Gln189Ter)	ATRIP	Pathogenic	criteria provided, single submitter
2948275	NM_033629.6(TREX1):c.366_367del (p.Ala123fs)	ATRIP	Pathogenic	criteria provided, single submitter
2952190	NM_033629.6(TREX1):c.141_151del (p.Pro48fs)	ATRIP	Pathogenic	criteria provided, single submitter
4179	NM_033629.6(TREX1):c.341G>A (p.Arg114His)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4180	NM_033629.6(TREX1):c.490C>T (p.Arg164Ter)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4184	NM_033629.6(TREX1):c.598G>A (p.Asp200Asn)	ATRIP	Pathogenic	criteria provided, single submitter
4185	NM_033629.6(TREX1):c.52G>A (p.Asp18Asn)	ATRIP	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · 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
TREX1	Strong	Autosomal dominant	retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TREX1	Orphanet:247691	Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations
TREX1	Orphanet:481662	Familial Chilblain lupus
TREX1	Orphanet:51	Aicardi-Goutières syndrome
TREX1	Orphanet:536	Systemic lupus erythematosus
ATRIP	Orphanet:808	Seckel syndrome

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
TREX1	HGNC:12269	ENSG00000213689	Q9NSU2	Three-prime repair exonuclease 1	gencc,clinvar
AMIGO3	HGNC:24075	ENSG00000176020	Q86WK7	Amphoterin-induced protein 3	clinvar
ATRIP	HGNC:33499	ENSG00000164053	Q8WXE1	ATR-interacting protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TREX1	Three-prime repair exonuclease 1	Major cellular 3’-to-5’ DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3’ termini.
AMIGO3	Amphoterin-induced protein 3	May mediate heterophilic cell-cell interaction.
ATRIP	ATR-interacting protein	Required for checkpoint signaling after DNA damage.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	9.7×	0.298
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TREX1	Enzyme (other)	yes	3.1.11.2	RNaseH-like_sf, Ribonucl_H, RNaseH_sf
AMIGO3	Antibody/Immunoglobulin	yes		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, Ig_sub2
ATRIP	Other/Unknown	no		ATRIP

Expression context

Cohort genes with no expression data: 0.

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
granulocyte	1
leukocyte	1
olfactory segment of nasal mucosa	1
hindlimb stylopod muscle	1
primordial germ cell in gonad	1
stromal cell of endometrium	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TREX1	134	ubiquitous	yes	olfactory segment of nasal mucosa, granulocyte, leukocyte
AMIGO3	129	broad	yes	primordial germ cell in gonad, hindlimb stylopod muscle, stromal cell of endometrium
ATRIP	170	ubiquitous	yes	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATRIP	1,544
TREX1	1,214
AMIGO3	778

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TREX1	Q9NSU2	12
ATRIP	Q8WXE1	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMIGO3	Q86WK7	73.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 3 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
Regulation by TREX1	1	5710.0×	0.005	TREX1
IRF3-mediated induction of type I IFN	1	407.9×	0.016	TREX1
Diseases of DNA Double-Strand Break Repair	1	407.9×	0.016	ATRIP
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	407.9×	0.016	ATRIP
Diseases of DNA repair	1	285.5×	0.016	ATRIP
Homologous DNA Pairing and Strand Exchange	1	190.3×	0.016	ATRIP
Homology Directed Repair	1	154.3×	0.016	ATRIP
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	154.3×	0.016	ATRIP
Impaired BRCA2 binding to RAD51	1	154.3×	0.016	ATRIP
Activation of ATR in response to replication stress	1	150.3×	0.016	ATRIP
HDR through Single Strand Annealing (SSA)	1	146.4×	0.016	ATRIP
Fanconi Anemia Pathway	1	139.3×	0.016	ATRIP
Presynaptic phase of homologous DNA pairing and strand exchange	1	135.9×	0.016	ATRIP
DNA Double-Strand Break Repair	1	124.1×	0.016	ATRIP
HDR through Homologous Recombination (HRR)	1	95.2×	0.020	ATRIP
G2/M Checkpoints	1	67.2×	0.024	ATRIP
Regulation of TP53 Activity	1	66.4×	0.024	ATRIP
G2/M DNA damage checkpoint	1	60.1×	0.024	ATRIP
Regulation of TP53 Activity through Phosphorylation	1	58.9×	0.024	ATRIP
Processing of DNA double-strand break ends	1	57.1×	0.024	ATRIP
DNA Repair	1	49.2×	0.027	ATRIP
Cell Cycle Checkpoints	1	44.3×	0.029	ATRIP
Transcriptional Regulation by TP53	1	31.0×	0.039	ATRIP
Cell Cycle	1	18.0×	0.064	ATRIP
RNA Polymerase II Transcription	1	11.3×	0.097	ATRIP
Gene expression (Transcription)	1	8.9×	0.117	ATRIP
Generic Transcription Pathway	1	7.5×	0.133	ATRIP
Disease	1	6.5×	0.147	ATRIP

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
immune response in brain or nervous system	1	5617.3×	0.004	TREX1
immune complex formation	1	5617.3×	0.004	TREX1
activation of immune response	1	2808.7×	0.004	TREX1
DNA modification	1	2808.7×	0.004	TREX1
DNA synthesis involved in UV-damage excision repair	1	2808.7×	0.004	TREX1
retrotransposition	1	1872.4×	0.005	TREX1
atrial cardiac muscle tissue development	1	1404.3×	0.005	TREX1
T cell antigen processing and presentation	1	1123.5×	0.005	TREX1
lymphoid progenitor cell differentiation	1	936.2×	0.005	TREX1
regulation of cellular respiration	1	936.2×	0.005	TREX1
regulation of lipid biosynthetic process	1	936.2×	0.005	TREX1
regulation of lysosome organization	1	936.2×	0.005	TREX1
DNA repair	2	42.6×	0.005	TREX1, ATRIP
regulation of immunoglobulin production	1	802.5×	0.005	TREX1
heart process	1	702.2×	0.005	TREX1
regulation of fatty acid metabolic process	1	624.1×	0.005	TREX1
regulation of T cell activation	1	624.1×	0.005	TREX1
regulation of type I interferon production	1	561.7×	0.005	TREX1
regulation of tumor necrosis factor production	1	561.7×	0.005	TREX1
cellular response to hydroxyurea	1	468.1×	0.006	TREX1
regulation of glycolytic process	1	401.2×	0.006	TREX1
macrophage activation involved in immune response	1	374.5×	0.006	TREX1
DNA metabolic process	1	351.1×	0.006	TREX1
mitotic G1 DNA damage checkpoint signaling	1	351.1×	0.006	TREX1
regulation of protein complex stability	1	351.1×	0.006	TREX1
negative regulation of cGAS/STING signaling pathway	1	351.1×	0.006	TREX1
inflammatory response to antigenic stimulus	1	312.1×	0.006	TREX1
DNA catabolic process	1	312.1×	0.006	TREX1
apoptotic cell clearance	1	295.6×	0.006	TREX1
negative regulation of type I interferon-mediated signaling pathway	1	255.3×	0.007	TREX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATRIP	3	3
TREX1	0	0
AMIGO3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERALASERTIB	3	ATRIP
ELIMUSERTIB	1	ATRIP
M4344	1	ATRIP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATRIP	31	Binding:31

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TREX1	3.1.11.2	exodeoxyribonuclease III

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

3 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)
CERALASERTIB	3	ATRIP
ELIMUSERTIB	1	ATRIP
M4344	1	ATRIP

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	ATRIP
C	Druggable family + PDB, no drug	1	TREX1
D	Druggable family + AlphaFold only, no drug	1	AMIGO3
E	Difficult family or no structure, no drug	0

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)
TREX1	0	—
AMIGO3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02723448	PHASE1	COMPLETED	Aclarubicin for the Treatment of Retinal Vasculopathy With Cerebral Leukodystrophy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ACLARUBICIN	3	1