Familial chilblain lupus

Summary

Familial chilblain lupus (MONDO:0018827) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	familial chilblain lupus
Mondo ID	MONDO:0018827
OMIM	610448
Orphanet	481662
UMLS	C5688224
MedGen	1807766
GARD	0017874
Is cancer (heuristic)	no

Also known as: hereditary Chilblain lupus · hereditary chilblain lupus

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › autoimmune disorder of cardiovascular system › chilblain lupus › familial chilblain lupus

Subtypes (2): chilblain lupus 1, chilblain lupus 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · 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
TREX1	Strong	Autosomal dominant	chilblain lupus 1	17
SAMHD1	Supportive	Autosomal dominant	familial chilblain lupus	9
STING1	Supportive	Autosomal dominant	familial chilblain lupus	6

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
SAMHD1	Orphanet:481662	Familial Chilblain lupus
SAMHD1	Orphanet:51	Aicardi-Goutières syndrome
STING1	Orphanet:425120	STING-associated vasculopathy with onset in infancy
STING1	Orphanet:481662	Familial Chilblain lupus

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
SAMHD1	HGNC:15925	ENSG00000101347	Q9Y3Z3	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	gencc
STING1	HGNC:27962	ENSG00000184584	Q86WV6	Stimulator of interferon genes protein	gencc

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.
SAMHD1	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks.
STING1	Stimulator of interferon genes protein	Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta).

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.482
Transcription factor	1	2.8×	0.482
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
SAMHD1	Transcription factor	no	3.1.5.B1	SAM, HD/PDEase_dom, HD_domain
STING1	Other/Unknown	no		STING, STING_C_sf, STING_C_chordates

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
granulocyte	2
olfactory segment of nasal mucosa	2
leukocyte	1
monocyte	1
mononuclear cell	1
pericardium	1
right uterine tube	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
SAMHD1	291	ubiquitous	marker	monocyte, mononuclear cell, pericardium
STING1	134	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, granulocyte

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SAMHD1	2,186
STING1	2,148
TREX1	1,214

Intra-cohort edges

A	B	Sources
SAMHD1	TREX1	string_interaction
STING1	TREX1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STING1	Q86WV6	119
SAMHD1	Q9Y3Z3	76
TREX1	Q9NSU2	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
IRF3-mediated induction of type I IFN	2	543.8×	1e-04	TREX1, STING1
Regulation by TREX1	1	3806.7×	0.003	TREX1
STAT6-mediated induction of chemokines	1	1268.9×	0.007	STING1
Nucleotide catabolism	1	423.0×	0.015	SAMHD1
STING mediated induction of host immune responses	1	346.1×	0.015	STING1
Regulation of innate immune responses to cytosolic DNA	1	253.8×	0.017	STING1
Dengue virus activates/modulates innate and adaptive immune responses	1	112.0×	0.029	STING1
Metabolism of nucleotides	1	100.2×	0.029	SAMHD1
Cytosolic sensors of pathogen-associated DNA	1	95.2×	0.029	STING1
SARS-CoV-1 activates/modulates innate immune responses	1	90.6×	0.029	STING1
SARS-CoV-1-host interactions	1	58.6×	0.037	STING1
Immune System	2	8.6×	0.037	SAMHD1, STING1
Interferon alpha/beta signaling	1	50.8×	0.039	SAMHD1
SARS-CoV-1 Infection	1	47.6×	0.039	STING1
Interferon Signaling	1	40.1×	0.041	SAMHD1
SARS-CoV-2-host interactions	1	39.6×	0.041	STING1
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	29.7×	0.051	STING1
SARS-CoV-2 Infection	1	26.8×	0.053	STING1
SARS-CoV Infections	1	18.5×	0.073	STING1
Cytokine Signaling in Immune system	1	13.6×	0.093	SAMHD1
Viral Infection Pathways	1	10.3×	0.117	STING1
Innate Immune System	1	8.5×	0.131	STING1
Infectious disease	1	8.3×	0.131	STING1
Neutrophil degranulation	1	7.7×	0.135	STING1
Disease	1	4.4×	0.221	STING1
Metabolism	1	3.9×	0.237	SAMHD1

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
negative regulation of type I interferon-mediated signaling pathway	2	510.7×	2e-04	TREX1, SAMHD1
defense response to virus	3	69.3×	2e-04	TREX1, SAMHD1, STING1
cellular response to interferon-beta	2	351.1×	3e-04	TREX1, STING1
regulation of inflammatory response	2	112.3×	0.002	TREX1, STING1
immune response in brain or nervous system	1	5617.3×	0.002	TREX1
immune complex formation	1	5617.3×	0.002	TREX1
activation of immune response	1	2808.7×	0.002	TREX1
dGTP catabolic process	1	2808.7×	0.002	SAMHD1
DNA modification	1	2808.7×	0.002	TREX1
deoxyribonucleotide catabolic process	1	2808.7×	0.002	SAMHD1
dATP catabolic process	1	2808.7×	0.002	SAMHD1
DNA synthesis involved in UV-damage excision repair	1	2808.7×	0.002	TREX1
retrotransposition	1	1872.4×	0.003	TREX1
atrial cardiac muscle tissue development	1	1404.3×	0.004	TREX1
T cell antigen processing and presentation	1	1123.5×	0.004	TREX1
cGAS/STING signaling pathway	1	1123.5×	0.004	STING1
lymphoid progenitor cell differentiation	1	936.2×	0.004	TREX1
regulation of cellular respiration	1	936.2×	0.004	TREX1
regulation of lipid biosynthetic process	1	936.2×	0.004	TREX1
regulation of lysosome organization	1	936.2×	0.004	TREX1
regulation of immunoglobulin production	1	802.5×	0.004	TREX1
heart process	1	702.2×	0.004	TREX1
protein localization to endoplasmic reticulum	1	702.2×	0.004	STING1
DNA strand resection involved in replication fork processing	1	702.2×	0.004	SAMHD1
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

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
STING1	PALBOCICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STING1	2	4
TREX1	0	0
SAMHD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	STING1
VADIMEZAN	3	STING1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
STING1	890	Binding:890
SAMHD1	4	Binding:3, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TREX1	3.1.11.2	exodeoxyribonuclease III
SAMHD1	3.1.5.B1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
STING1	890

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

2 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)
PALBOCICLIB	4	STING1
VADIMEZAN	3	STING1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STING1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TREX1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SAMHD1

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	—
SAMHD1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.