Chilblain lupus

Summary

Chilblain lupus (MONDO:0019557) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		70	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0000965	Cutis marmorata	Frequent (30-79%)
HP:0000988	Skin rash	Frequent (30-79%)
HP:0002923	Rheumatoid factor positive	Frequent (30-79%)
HP:0010702	Increased circulating antibody level	Frequent (30-79%)
HP:0011123	Inflammatory abnormality of the skin	Frequent (30-79%)
HP:0025131	Finger swelling	Frequent (30-79%)
HP:0025300	Malar rash	Frequent (30-79%)
HP:0030350	Erythematous papule	Frequent (30-79%)
HP:0030880	Raynaud phenomenon	Frequent (30-79%)
HP:0030899	Pruritis on hand	Frequent (30-79%)
HP:0200042	Skin ulcer	Frequent (30-79%)
HP:0002099	Asthma	Occasional (5-29%)
HP:0002725	Systemic lupus erythematosus	Occasional (5-29%)
HP:0003493	Antinuclear antibody positivity	Occasional (5-29%)
HP:0003613	Antiphospholipid antibody positivity	Occasional (5-29%)
HP:0007417	Discoid lupus rash	Occasional (5-29%)
HP:0012325	Chronic myelomonocytic leukemia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	chilblain lupus
Mondo ID	MONDO:0019557
Orphanet	90280
DOID	DOID:0060386
UMLS	C4551515
MedGen	1632142
GARD	0019130
MedDRA	10025141
Is cancer (heuristic)	no

Also known as: CHLE · Hutchinson lupus

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

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

Related subtypes (5): rheumatic pulmonary valve disease, autoimmune cardiomyopathy, autoimmune atherosclerosis, autoimmune vasculitis, Libman-Sacks endocarditis

Subtypes (1): familial chilblain lupus

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

2 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4185	NM_033629.6(TREX1):c.52G>A (p.Asp18Asn)	ATRIP	Pathogenic	criteria provided, multiple submitters, no conflicts
4183	NM_033629.6(TREX1):c.375dup (p.Gly126fs)	ATRIP	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATRIP	Orphanet:808	Seckel syndrome

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
ATRIP	HGNC:33499	ENSG00000164053	Q8WXE1	ATR-interacting protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATRIP	ATR-interacting protein	Required for checkpoint signaling after DNA damage.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATRIP	Q8WXE1	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. 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
Diseases of DNA Double-Strand Break Repair	1	815.7×	0.009	ATRIP
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	815.7×	0.009	ATRIP
Diseases of DNA repair	1	571.0×	0.009	ATRIP
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.009	ATRIP
Homology Directed Repair	1	308.6×	0.009	ATRIP
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	308.6×	0.009	ATRIP
Impaired BRCA2 binding to RAD51	1	308.6×	0.009	ATRIP
Activation of ATR in response to replication stress	1	300.5×	0.009	ATRIP
HDR through Single Strand Annealing (SSA)	1	292.8×	0.009	ATRIP
Fanconi Anemia Pathway	1	278.5×	0.009	ATRIP
Presynaptic phase of homologous DNA pairing and strand exchange	1	271.9×	0.009	ATRIP
DNA Double-Strand Break Repair	1	248.3×	0.009	ATRIP
HDR through Homologous Recombination (HRR)	1	190.3×	0.011	ATRIP
G2/M Checkpoints	1	134.3×	0.013	ATRIP
Regulation of TP53 Activity	1	132.8×	0.013	ATRIP
G2/M DNA damage checkpoint	1	120.2×	0.013	ATRIP
Regulation of TP53 Activity through Phosphorylation	1	117.7×	0.013	ATRIP
Processing of DNA double-strand break ends	1	114.2×	0.013	ATRIP
DNA Repair	1	98.5×	0.014	ATRIP
Cell Cycle Checkpoints	1	88.5×	0.015	ATRIP
Transcriptional Regulation by TP53	1	62.1×	0.020	ATRIP
Cell Cycle	1	36.0×	0.033	ATRIP
RNA Polymerase II Transcription	1	22.5×	0.050	ATRIP
Gene expression (Transcription)	1	17.8×	0.061	ATRIP
Generic Transcription Pathway	1	15.1×	0.069	ATRIP
Disease	1	13.1×	0.076	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of double-strand break repair	1	581.1×	0.003	ATRIP
nucleobase-containing compound metabolic process	1	526.6×	0.003	ATRIP
DNA damage checkpoint signaling	1	391.9×	0.003	ATRIP
DNA repair	1	63.8×	0.016	ATRIP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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): 0.

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

Symbol	Assays	Type breakdown
ATRIP	31	Binding:31

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.