Sneddon syndrome

Summary

Sneddon syndrome (MONDO:0008436) is a disease with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 144
• Phenotypes (HPO): 54
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.4	Europe	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0033260	Livedo racemosa	Obligate (100%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0000965	Cutis marmorata	Very frequent (80-99%)
HP:0001727	Thromboembolic stroke	Very frequent (80-99%)
HP:0002076	Migraine	Very frequent (80-99%)
HP:0002120	Cerebral cortical atrophy	Very frequent (80-99%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0002321	Vertigo	Very frequent (80-99%)
HP:0002354	Memory impairment	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0011276	Vascular skin abnormality	Very frequent (80-99%)
HP:0100545	Arterial stenosis	Very frequent (80-99%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0001123	Visual field defect	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001269	Hemiparesis	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001653	Mitral regurgitation	Frequent (30-79%)
HP:0001659	Aortic regurgitation	Frequent (30-79%)
HP:0002326	Transient ischemic attack	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0007359	Focal-onset seizure	Frequent (30-79%)
HP:0010794	Impaired visuospatial constructive cognition	Frequent (30-79%)
HP:0011714	Libman-Sacks lesions	Frequent (30-79%)
HP:0012213	Decreased glomerular filtration rate	Frequent (30-79%)
HP:0025722	Cerebral infarct	Frequent (30-79%)
HP:0031987	Diminished ability to concentrate	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0100576	Amaurosis fugax	Frequent (30-79%)
HP:0000093	Proteinuria	Occasional (5-29%)
HP:0000112	Nephropathy	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001647	Bicuspid aortic valve	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002381	Aphasia	Occasional (5-29%)
HP:0003613	Antiphospholipid antibody positivity	Occasional (5-29%)
HP:0009710	Chilblains	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0012246	Oculomotor nerve palsy	Occasional (5-29%)
HP:0020166	Central retinal vein occlusion	Occasional (5-29%)
HP:0025342	Central retinal artery occlusion	Occasional (5-29%)
HP:0030773	Internuclear ophthalmoplegia	Occasional (5-29%)
HP:0030880	Raynaud phenomenon	Occasional (5-29%)
HP:0033126	Cutaneous necrosis	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Sneddon syndrome
Mondo ID	MONDO:0008436
EFO	EFO:1001186
MeSH	D018860
OMIM	182410
Orphanet	820
DOID	DOID:13096
ICD-11	1474816492
SNOMED CT	238776001
UMLS	C0282492
MedGen	76449
GARD	0007664
MedDRA	10053841
NORD	1726
Is cancer (heuristic)	no

Also known as: cerebro-vascular lesions and livedo reticularis · Ehrmann-Sneddon syndrome · livedo racemosa and cerebrovascular accidents · livedo racemosa-cerebrovascular accident syndrome · livedo reticularis-cerebrovascular accident syndrome · Sneddon syndrome · Sneddon’s syndrome

Data availability: 144 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › arterial disorder › Sneddon syndrome

Related subtypes (29): vertebral artery insufficiency, splenic artery aneurysm, basilar artery insufficiency, arteriosclerosis disorder, subclavian artery aneurysm, pulmonary artery choriocarcinoma, pulmonary artery leiomyosarcoma, coronary artery disorder, hypertensive disorder, carotid artery disorder, pulmonary embolism, peripheral arterial disease, hypotensive disorder, large artery stroke, aortic disorder, cervical artery dissection, anterior spinal artery syndrome, fibromuscular dysplasia, retinal arterial tortuosity, celiac trunk compression syndrome, pediatric arterial ischemic stroke, absence of the pulmonary artery, arterial occlusion, aberrant subclavian artery, anterior spinal artery stroke, arteritis, pulmonary artery disease, fibromuscular dysplasia, multifocal, carotid web

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

144 retrieved; paginated sample, class counts are floors:

82 uncertain significance, 15 pathogenic/likely pathogenic, 15 conflicting classifications of pathogenicity, 14 likely benign, 10 pathogenic, 7 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027878	NM_001282225.2(ADA2):c.1373T>A (p.Val458Asp)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033820	NM_001282225.2(ADA2):c.1040del (p.Asp347fs)	ADA2	Pathogenic	criteria provided, single submitter
1076271	NM_001282225.2(ADA2):c.139G>C (p.Gly47Arg)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1171011	NM_001282225.2(ADA2):c.631TTC[1] (p.Phe212del)	ADA2	Pathogenic	no assertion criteria provided
120299	NM_001282225.2(ADA2):c.1358A>G (p.Tyr453Cys)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120301	NM_001282225.2(ADA2):c.140G>C (p.Gly47Ala)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
120303	NM_001282225.2(ADA2):c.506G>A (p.Arg169Gln)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120304	NM_001282225.2(ADA2):c.139G>A (p.Gly47Arg)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120305	NM_001282225.2(ADA2):c.752C>T (p.Pro251Leu)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120306	NM_001282225.2(ADA2):c.140G>T (p.Gly47Val)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1392821	NM_001282225.2(ADA2):c.753G>A (p.Pro251=)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1411116	NM_001282225.2(ADA2):c.940_941del (p.Lys314fs)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189342	NM_001282225.2(ADA2):c.1078A>G (p.Thr360Ala)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
189343	NM_001282225.2(ADA2):c.1147G>A (p.Gly383Ser)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2889771	NM_001282225.2(ADA2):c.660C>A (p.Tyr220Ter)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
3587771	NM_001282225.2(ADA2):c.794C>G (p.Ser265Ter)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
541735	NM_001282225.2(ADA2):c.973-2A>G	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
586963	NM_001282225.2(ADA2):c.144dup (p.Arg49fs)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
640066	NM_001282225.2(ADA2):c.144del (p.Arg49fs)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
645215	NM_001282225.2(ADA2):c.661_664del (p.Ala221fs)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
827684	NM_001282225.2(ADA2):c.1110C>A (p.Asn370Lys)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
852411	NM_001282225.2(ADA2):c.934C>T (p.Arg312Ter)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
860051	NM_001282225.2(ADA2):c.1397_1403del (p.Lys466fs)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956376	NM_001282225.2(ADA2):c.505C>T (p.Arg169Trp)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447832	NM_000435.3(NOTCH3):c.3296G>A (p.Cys1099Tyr)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1691821	NM_001282225.2(ADA2):c.548T>C (p.Leu183Pro)	ADA2	Likely pathogenic	criteria provided, single submitter
3587763	NM_001282225.2(ADA2):c.1201A>T (p.Lys401Ter)	ADA2	Likely pathogenic	criteria provided, single submitter
3587767	NM_001282225.2(ADA2):c.972+1G>C	ADA2	Likely pathogenic	criteria provided, single submitter
3587774	NM_001282225.2(ADA2):c.368G>A (p.Trp123Ter)	ADA2	Likely pathogenic	criteria provided, single submitter
3587776	NM_001282225.2(ADA2):c.71dup (p.Gly25fs)	ADA2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 6 · 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
ADA2	Moderate	Autosomal recessive	Sneddon syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADA2	Orphanet:124	Diamond-Blackfan anemia
ADA2	Orphanet:404553	Deficiency of adenosine deaminase 2
ADA2	Orphanet:820	Sneddon syndrome
NOTCH3	Orphanet:136	Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy
NOTCH3	Orphanet:2591	Infantile myofibromatosis
NOTCH3	Orphanet:2789	Lateral meningocele syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADA2	HGNC:1839	ENSG00000093072	Q9NZK5	Adenosine deaminase 2	gencc,clinvar
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADA2	Adenosine deaminase 2	Adenosine deaminase that may contribute to the degradation of extracellular adenosine, a signaling molecule that controls a variety of cellular responses.
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADA2	Enzyme (other)	yes	3.5.4.4	A_deaminase_dom, Ado/ade_deaminase, ADGF
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
popliteal artery	1
right coronary artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADA2	254	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
NOTCH3	273	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH3	4,403
ADA2	1,808

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH3	Q9UM47	6
ADA2	Q9NZK5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 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×	0.006	NOTCH3
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	951.7×	0.006	NOTCH3
Noncanonical activation of NOTCH3	1	713.8×	0.006	NOTCH3
Pre-NOTCH Processing in Golgi	1	317.2×	0.009	NOTCH3
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.009	NOTCH3
NOTCH3 Intracellular Domain Regulates Transcription	1	219.6×	0.009	NOTCH3
Notch-HLH transcription pathway	1	203.9×	0.009	NOTCH3
Surfactant metabolism	1	184.2×	0.009	ADA2
Pre-NOTCH Transcription and Translation	1	61.4×	0.023	NOTCH3
Innate Immune System	1	12.8×	0.100	ADA2
Neutrophil degranulation	1	11.5×	0.100	ADA2
Immune System	1	6.5×	0.155	ADA2
Metabolism of proteins	1	6.2×	0.155	ADA2

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
inosine biosynthetic process	1	2808.7×	0.002	ADA2
glomerular capillary formation	1	2808.7×	0.002	NOTCH3
adenosine catabolic process	1	2106.5×	0.002	ADA2
neuroblast differentiation	1	1053.2×	0.003	NOTCH3
neuron fate commitment	1	401.2×	0.007	NOTCH3
artery morphogenesis	1	337.0×	0.007	NOTCH3
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×	0.026	NOTCH3
negative regulation of transcription by RNA polymerase II	1	8.9×	0.118	NOTCH3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	NOTCH3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
ADA2	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): 1.

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

Symbol	Assays	Type breakdown
NOTCH3	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADA2	3.5.4.4	adenosine deaminase

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	1	ADA2
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)
ADA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06935578	Not specified	RECRUITING	RAre, But Not aLone: a Large Italian Network to Empower the Impervious diaGNostic Pathway of Rare cerEbrovascular Diseases (ALIGNED)
NCT06850519	Not specified	COMPLETED	Genetic Risk Factors of the Sneddon Syndrome