Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Summary

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (MONDO:0000914) is a disease caused by NOTCH3 (GenCC Definitive), with 3 cohort genes and 28 clinical trials. Top therapeutic interventions include cilostazol, dabigatran etexilate, and fremanezumab.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: NOTCH3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 427
• Phenotypes (HPO): 40
• Clinical trials: 28

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3	Europe	Validated
Point prevalence	1-9 / 100 000	2	United Kingdom	Validated
Point prevalence	1-9 / 100 000	3	Finland	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0002352	Leukoencephalopathy	Very frequent (80-99%)
HP:0002500	Abnormal cerebral white matter morphology	Very frequent (80-99%)
HP:0032325	Lacunar stroke	Very frequent (80-99%)
HP:0040329	Multifocal hyperintensity of cerebral white matter on MRI	Very frequent (80-99%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000741	Apathy	Frequent (30-79%)
HP:0001297	Stroke	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0002077	Migraine with aura	Frequent (30-79%)
HP:0002326	Transient ischemic attack	Frequent (30-79%)
HP:0002637	Cerebral ischemia	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0001342	Cerebral hemorrhage	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002140	Ischemic stroke	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002301	Hemiplegia	Occasional (5-29%)
HP:0002333	Motor deterioration	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002463	Language impairment	Occasional (5-29%)
HP:0007185	Loss of consciousness	Occasional (5-29%)
HP:0007236	Recurrent subcortical infarcts	Occasional (5-29%)
HP:0010794	Impaired visuospatial constructive cognition	Occasional (5-29%)
HP:0010992	Stress urinary incontinence	Occasional (5-29%)
HP:0012444	Brain atrophy	Occasional (5-29%)
HP:0031843	Bradyphrenia	Occasional (5-29%)
HP:0100545	Arterial stenosis	Occasional (5-29%)
HP:0002381	Aphasia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Mondo ID	MONDO:0000914
MeSH	D046589
OMIM	125310
Orphanet	136
DOID	DOID:0111035
ICD-11	1621899838
NCIT	C84606
SNOMED CT	390936003
UMLS	C4551768
MedGen	1634330
GARD	0001049
MedDRA	10065551
NORD	883
Is cancer (heuristic)	no

Also known as: autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 1 · CADASIL · CADASIL syndrome · CADASIL type 1 · CADASIL1 · CASIL · cerebral arteriopathy with subcortical infarcts and leukoencephalopathy · cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 · cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 · cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy · dementia, hereditary multi-infarct type · familial vascular leukoencephalopathy · hereditary multi-infarct dementia

Data availability: 427 ClinVar variants · 5 GenCC gene-disease records · 11 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Related subtypes (191): autosomal dominant polycystic liver disease, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

427 retrieved; paginated sample, class counts are floors:

110 uncertain significance, 89 conflicting classifications of pathogenicity, 49 benign, 46 pathogenic, 40 pathogenic/likely pathogenic, 36 benign/likely benign, 33 likely pathogenic, 23 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
447827	NM_000435.3(NOTCH3):c.3091C>T (p.Arg1031Cys)	MIR6795	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173096	NM_000435.3(NOTCH3):c.698G>A (p.Cys233Tyr)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1298355	NM_000435.3(NOTCH3):c.1492G>T (p.Gly498Cys)	NOTCH3	Pathogenic	no assertion criteria provided
1333478	NM_000435.3(NOTCH3):c.1624T>C (p.Cys542Arg)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1365706	NM_000435.3(NOTCH3):c.194G>A (p.Cys65Tyr)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709532	NM_000435.3(NOTCH3):c.2963G>A (p.Cys988Tyr)	NOTCH3	Pathogenic	criteria provided, single submitter
1709694	NM_000435.3(NOTCH3):c.547T>A (p.Cys183Ser)	NOTCH3	Pathogenic	criteria provided, single submitter
1709971	NM_000435.3(NOTCH3):c.699T>G (p.Cys233Trp)	NOTCH3	Pathogenic	criteria provided, single submitter
1803216	NM_000435.3(NOTCH3):c.431G>T (p.Cys144Phe)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805526	NM_000435.3(NOTCH3):c.1791C>G (p.Cys597Trp)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1879844	NM_000435.3(NOTCH3):c.341-1G>C	NOTCH3	Pathogenic	criteria provided, single submitter
1879845	NM_000435.3(NOTCH3):c.1136G>A (p.Cys379Tyr)	NOTCH3	Pathogenic	criteria provided, single submitter
208501	NM_000435.3(NOTCH3):c.457C>T (p.Arg153Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
217882	NM_000435.3(NOTCH3):c.1187C>G (p.Ser396Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
2572441	NM_000435.3(NOTCH3):c.4360del (p.Asp1454fs)	NOTCH3	Pathogenic	criteria provided, single submitter
2736837	NM_000435.3(NOTCH3):c.617G>A (p.Cys206Tyr)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280277	NM_000435.3(NOTCH3):c.1364G>T (p.Cys455Phe)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
3075663	NM_000435.3(NOTCH3):c.521G>C (p.Cys174Ser)	NOTCH3	Pathogenic	criteria provided, single submitter
3380914	NM_000435.3(NOTCH3):c.1531T>C (p.Cys511Arg)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3571609	NM_000435.3(NOTCH3):c.812G>T (p.Cys271Phe)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
374637	NM_000435.3(NOTCH3):c.1819C>T (p.Arg607Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3899394	NM_000435.3(NOTCH3):c.382T>G (p.Cys128Gly)	NOTCH3	Pathogenic	criteria provided, single submitter
3899395	NM_000435.3(NOTCH3):c.953G>T (p.Cys318Phe)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4076096	NOTCH3, ARG544CYS	NOTCH3	Pathogenic	no assertion criteria provided
4076097	NOTCH3, ARG578CYS	NOTCH3	Pathogenic	no assertion criteria provided
4076098	G528C	NOTCH3	Pathogenic	no assertion criteria provided
4277433	NM_000435.3(NOTCH3):c.2410G>T (p.Gly804Cys)	NOTCH3	Pathogenic	criteria provided, single submitter
4281622	NM_000435.3(NOTCH3):c.872G>A (p.Cys291Tyr)	NOTCH3	Pathogenic	criteria provided, single submitter
4281643	NM_000435.3(NOTCH3):c.1012T>A (p.Cys338Ser)	NOTCH3	Pathogenic	criteria provided, single submitter
4281677	NM_000435.3(NOTCH3):c.401G>A (p.Cys134Tyr)	NOTCH3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 8 · 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
NOTCH3	Definitive	Autosomal dominant	cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOTCH3	Orphanet:136	Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy
NOTCH3	Orphanet:2591	Infantile myofibromatosis
NOTCH3	Orphanet:2789	Lateral meningocele syndrome
OFD1	Orphanet:244	Primary ciliary dyskinesia
OFD1	Orphanet:2750	Orofaciodigital syndrome type 1
OFD1	Orphanet:2754	Orofaciodigital syndrome type 6
OFD1	Orphanet:475	Isolated Joubert syndrome
OFD1	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	gencc,clinvar
OFD1	HGNC:2567	ENSG00000046651	O75665	Centriole and centriolar satellite protein OFD1	clinvar
MIR6795	HGNC:50031	ENSG00000275711		microRNA 6795	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.
OFD1	Centriole and centriolar satellite protein OFD1	Component of the centrioles controlling mother and daughter centrioles length.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
OFD1	Other/Unknown	no		LisH, OFD1
MIR6795	Other/Unknown	no

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
popliteal artery	1
right coronary artery	1
tibial artery	1
bronchial epithelial cell	1
cervix squamous epithelium	1
sperm	1
intestine	1
stomach	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOTCH3	273	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery
OFD1	288	ubiquitous	marker	sperm, bronchial epithelial cell, cervix squamous epithelium
MIR6795	34		yes	sural nerve, intestine, stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH3	4,403
OFD1	2,878
MIR6795	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH3	Q9UM47	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OFD1	O75665	68.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Defective LFNG causes SCDO3	1	1142.0×	0.007	NOTCH3
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	951.7×	0.007	NOTCH3
Noncanonical activation of NOTCH3	1	713.8×	0.007	NOTCH3
Pre-NOTCH Processing in Golgi	1	317.2×	0.011	NOTCH3
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.011	NOTCH3
NOTCH3 Intracellular Domain Regulates Transcription	1	219.6×	0.011	NOTCH3
Notch-HLH transcription pathway	1	203.9×	0.011	NOTCH3
Hedgehog ‘off’ state	1	89.2×	0.018	OFD1
Loss of Nlp from mitotic centrosomes	1	79.3×	0.018	OFD1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.018	OFD1
AURKA Activation by TPX2	1	76.1×	0.018	OFD1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.018	OFD1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.018	OFD1
Pre-NOTCH Transcription and Translation	1	61.4×	0.018	NOTCH3
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.018	OFD1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.018	OFD1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete negative regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation	1	4213.0×	0.003	OFD1
glomerular capillary formation	1	2808.7×	0.003	NOTCH3
embryonic body morphogenesis	1	1053.2×	0.004	OFD1
neuroblast differentiation	1	1053.2×	0.004	NOTCH3
epithelial cilium movement involved in determination of left/right asymmetry	1	648.1×	0.005	OFD1
neuron fate commitment	1	401.2×	0.007	NOTCH3
artery morphogenesis	1	337.0×	0.007	NOTCH3
axoneme assembly	1	271.8×	0.008	OFD1
forebrain development	1	175.5×	0.010	NOTCH3
positive regulation of smooth muscle cell proliferation	1	165.2×	0.010	NOTCH3
positive regulation of miRNA transcription	1	145.3×	0.010	NOTCH3
negative regulation of neuron differentiation	1	135.9×	0.010	NOTCH3
Notch signaling pathway	1	70.8×	0.018	NOTCH3
axon guidance	1	45.3×	0.027	NOTCH3
cilium assembly	1	36.8×	0.031	OFD1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.117	NOTCH3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	NOTCH3

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Dabigatran, Sodium Chloride.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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
NOTCH3	1	2
OFD1	0	0
MIR6795	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH3	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
VAREGACESTAT	2	NOTCH3

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	NOTCH3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	OFD1, MIR6795

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)
OFD1	0	—
MIR6795	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	22
PHASE2	5
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04753970	PHASE1/PHASE2	RECRUITING	Retina is a Marker for Cerebrovascular Heath
NCT05755997	PHASE2	ACTIVE_NOT_RECRUITING	CERebrolysin In CADASIL
NCT01361763	PHASE2	UNKNOWN	Safety Study of Dabigatran in CADASIL
NCT04334408	PHASE2	WITHDRAWN	Safety and Efficacy of Fremanezumab for Migraine in Adult CADASIL
NCT04658823	PHASE2	COMPLETED	Efficacy and Safety of Tocotrienols in CADASIL
NCT06072118	PHASE2	COMPLETED	Adrenomedullin for CADASIL
NCT02795052	Not specified	RECRUITING	Neurologic Stem Cell Treatment Study
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT04310098	Not specified	RECRUITING	CADASIL Registry Study
NCT05473637	Not specified	RECRUITING	Taiwan Associated Genetic and Nongenetic Small Vessel Disease
NCT05491980	Not specified	ACTIVE_NOT_RECRUITING	Florida Cerebrovascular Disease Biorepository and Genomics Center
NCT05677880	Not specified	RECRUITING	Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Study
NCT05734378	Not specified	RECRUITING	Prognosis of Cerebral Small Vessel Disease
NCT06148051	Not specified	RECRUITING	AusCADASIL: An Australian Cohort of CADASIL
NCT06859658	Not specified	NOT_YET_RECRUITING	Development and Validation of a Functional MRI Biomarker of Cerebral Small Vessel Dysfunction in CADASIL
NCT06935578	Not specified	RECRUITING	RAre, But Not aLone: a Large Italian Network to Empower the Impervious diaGNostic Pathway of Rare cerEbrovascular Diseases (ALIGNED)
NCT06938100	Not specified	RECRUITING	Genotype, Clinical Features and Imaging of Neuroradiological Abnormalities in CADASIL
NCT07497867	Not specified	RECRUITING	Long-term Prospective Study of Korean CADASIL Patients
NCT01114815	Not specified	COMPLETED	Research Study on Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)
NCT01865604	Not specified	COMPLETED	Impact of tDCS on Cerebral Autoregulation
NCT02032225	Not specified	COMPLETED	Generation of a Cellular Model of CADASIL From Skin Fibroblasts
NCT02071784	Not specified	COMPLETED	Imaging Study of Neurovascular Coupling in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02837354	Not specified	COMPLETED	The Silent Cortical Infarcts in the Cerebral Amyloid Angiopathy: Is There a Link With Subarachnoid Hemorrhage?
NCT03724136	Not specified	UNKNOWN	Alzheimer’s Autism and Cognitive Impairment Stem Cell Treatment Study
NCT04036084	Not specified	UNKNOWN	Development of New Biomarkers With Magnetic Resonance Imaging for Longitudinal Studies in CADASIL Angiopathy
NCT05793424	Not specified	UNKNOWN	Establishment of a CSF Bank for the Development of Biomarkers of Smooth Muscle Cell (SMC) Damage in Monogenic Cerebral Small Vessel Disease
NCT05902039	Not specified	UNKNOWN	MRI Study of Blood-brain Barrier Function in CADASIL

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CILOSTAZOL	4	1
DABIGATRAN ETEXILATE	4	1
FREMANEZUMAB	4	1
DABIGATRAN	3	1
ADRENOMEDULLIN	2	1