Cold-induced sweating syndrome 1

Summary

Cold-induced sweating syndrome 1 (MONDO:0010091) is a disease caused by CRLF1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CRLF1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 34
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000293	Full cheeks	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000445	Wide nose	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000966	Hypohidrosis	Very frequent (80-99%)
HP:0000975	Hyperhidrosis	Very frequent (80-99%)
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0001371	Flexion contracture	Very frequent (80-99%)
HP:0001522	Death in infancy	Very frequent (80-99%)
HP:0001645	Sudden cardiac death	Very frequent (80-99%)
HP:0002047	Malignant hyperthermia	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002808	Kyphosis	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0100490	Camptodactyly of finger	Very frequent (80-99%)
HP:0100729	Large face	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Cold-induced sweating syndrome 1
Mondo ID	MONDO:0010091
MeSH	C536214
OMIM	272430, 601378
Orphanet	1545
DOID	DOID:0080329
SNOMED CT	725097006
UMLS	C1848947
MedGen	338577
GARD	0001611
Is cancer (heuristic)	no

Also known as: CISS1 · cold-induced sweating syndrome type 1 · Crisponi syndrome

Data availability: 34 ClinVar variants · 5 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › sensory peripheral neuropathy › hereditary sensory and autonomic neuropathy › cold-induced sweating syndrome - hyperthermia spectrum › cold-induced sweating syndrome › Cold-induced sweating syndrome 1

Related subtypes (2): cold-induced sweating syndrome 2, PERCHING 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

34 retrieved; paginated sample, class counts are floors:

20 pathogenic, 7 likely pathogenic, 4 uncertain significance, 1 not provided, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5706	NM_004750.4(CRLF1):c.[242G>A;1121T>G]		Pathogenic	no assertion criteria provided
1322162	NM_004750.5(CRLF1):c.31_53del (p.Gln11fs)	CRLF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1526164	NM_004750.5(CRLF1):c.776C>A (p.Ser259Ter)	CRLF1	Pathogenic	criteria provided, single submitter
1676590	NM_004750.5(CRLF1):c.713del (p.Pro238fs)	CRLF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1694460	NM_004750.5(CRLF1):c.771G>A (p.Trp257Ter)	CRLF1	Pathogenic	criteria provided, single submitter
21008	NM_004750.5(CRLF1):c.857_864del (p.Val286fs)	CRLF1	Pathogenic	no assertion criteria provided
216913	NM_004750.5(CRLF1):c.713dup (p.Pro239fs)	CRLF1	Pathogenic	criteria provided, multiple submitters, no conflicts
224612	NM_004750.5(CRLF1):c.845_846del (p.Val282fs)	CRLF1	Pathogenic	no assertion criteria provided
2504415	NM_004750.5(CRLF1):c.397+1G>A	CRLF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775479	NM_004750.5(CRLF1):c.756_757del (p.Gln252fs)	CRLF1	Pathogenic	criteria provided, single submitter
418665	NM_004750.5(CRLF1):c.983dup (p.Ser328fs)	CRLF1	Pathogenic	criteria provided, multiple submitters, no conflicts
5707	NM_004750.5(CRLF1):c.676dup (p.Thr226fs)	CRLF1	Pathogenic	criteria provided, single submitter
5708	NM_004750.5(CRLF1):c.226T>G (p.Trp76Gly)	CRLF1	Pathogenic	no assertion criteria provided
5711	NM_004750.5(CRLF1):c.1102A>T (p.Lys368Ter)	CRLF1	Pathogenic	no assertion criteria provided
5712	NM_004750.5(CRLF1):c.708_709delinsT (p.Pro238fs)	CRLF1	Pathogenic	no assertion criteria provided
816854	NM_004750.5(CRLF1):c.985dup (p.Glu329fs)	CRLF1	Pathogenic	no assertion criteria provided
929438	NM_004750.5(CRLF1):c.531G>A (p.Trp177Ter)	CRLF1	Pathogenic	criteria provided, multiple submitters, no conflicts
226127	NM_001031710.3(KLHL7):c.1261T>A (p.Cys421Ser)	KLHL7	Pathogenic	no assertion criteria provided
226129	NM_001031710.3(KLHL7):c.1022del (p.Leu341fs)	KLHL7	Pathogenic	no assertion criteria provided
226130	NM_001031710.3(KLHL7):c.1115G>A (p.Arg372Gln)	KLHL7	Pathogenic	no assertion criteria provided
5713	NM_004750.5(CRLF1):c.829C>T (p.Arg277Ter)	LOC112543470	Pathogenic	no assertion criteria provided
1676201	NM_004750.5(CRLF1):c.167T>C (p.Leu56Pro)	CRLF1	Likely pathogenic	no assertion criteria provided
2572024	NM_004750.5(CRLF1):c.824G>C (p.Arg275Pro)	CRLF1	Likely pathogenic	criteria provided, single submitter
3362563	NM_004750.5(CRLF1):c.605del (p.Ala202fs)	CRLF1	Likely pathogenic	criteria provided, single submitter
3362860	NM_004750.5(CRLF1):c.828_831del (p.Arg275_Tyr276insTer)	CRLF1	Likely pathogenic	criteria provided, single submitter
3583543	NM_004750.5(CRLF1):c.1213-1G>T	CRLF1	Likely pathogenic	criteria provided, single submitter
3583544	NM_004750.5(CRLF1):c.855+2T>G	CRLF1	Likely pathogenic	criteria provided, single submitter
929437	NM_004750.5(CRLF1):c.935G>T (p.Arg312Leu)	CRLF1	Likely pathogenic	criteria provided, single submitter
226128	NM_001031710.3(KLHL7):c.1258C>T (p.Arg420Cys)	KLHL7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779177	NM_004750.5(CRLF1):c.193G>C (p.Asp65His)	CRLF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 10 · 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
CRLF1	Definitive	Autosomal recessive	Cold-induced sweating syndrome 1	6
CLCF1	Strong	Autosomal recessive	cold-induced sweating syndrome 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRLF1	Orphanet:1545	Crisponi syndrome
CRLF1	Orphanet:157820	Cold-induced sweating syndrome
CRLF1	Orphanet:930	Idiopathic achalasia
CLCF1	Orphanet:1545	Crisponi syndrome
CLCF1	Orphanet:157820	Cold-induced sweating syndrome
KLHL7	Orphanet:157820	Cold-induced sweating syndrome
KLHL7	Orphanet:603684	KLHL7-related Bohring-Opitz-like and Crisponi/Cold-induced sweating-like overlap syndrome
KLHL7	Orphanet:603689	KLHL7-related Bohring-Opitz-like syndrome
KLHL7	Orphanet:603694	KLHL7-related Crisponi/cold-induced sweating-like syndrome
KLHL7	Orphanet:791	Retinitis pigmentosa

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
CRLF1	HGNC:2364	ENSG00000006016	O75462	Cytokine receptor-like factor 1	gencc,clinvar
CLCF1	HGNC:17412	ENSG00000175505	Q9UBD9	Cardiotrophin-like cytokine factor 1	gencc
KLHL7	HGNC:15646	ENSG00000122550	Q8IXQ5	Kelch-like protein 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRLF1	Cytokine receptor-like factor 1	In complex with CLCF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development.
CLCF1	Cardiotrophin-like cytokine factor 1	In complex with CRLF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development.
KLHL7	Kelch-like protein 7	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRLF1	Antibody/Immunoglobulin	yes	1.1.1.105	FN3_dom, Ig-like_fold, Growth/epo_recpt_lig-bind
CLCF1	Other/Unknown	no		4_helix_cytokine-like_core, PRF/CT
KLHL7	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

Expression context

Cohort genes with no expression data: 0.

3 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
left uterine tube	1
male germ line stem cell (sensu Vertebrata) in testis	1
metanephros cortex	1
heart right ventricle	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRLF1	227	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
CLCF1	187	ubiquitous	marker	left uterine tube, metanephros cortex, male germ line stem cell (sensu Vertebrata) in testis
KLHL7	274	ubiquitous	marker	oocyte, secondary oocyte, heart right ventricle

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KLHL7	1,123
CRLF1	589
CLCF1	491

Intra-cohort edges

A	B	Sources
CLCF1	CRLF1	intact, string_interaction
CRLF1	KLHL7	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCF1	Q9UBD9	2
CRLF1	O75462	1
KLHL7	Q8IXQ5	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
IL-6-type cytokine receptor ligand interactions	2	634.4×	5e-06	CRLF1, CLCF1
Interleukin-27 signaling	1	519.1×	0.002	CRLF1

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
cell surface receptor signaling pathway via STAT	2	374.5×	1e-04	CRLF1, CLCF1
cytokine-mediated signaling pathway	2	87.1×	0.001	CRLF1, CLCF1
negative regulation of neuron apoptotic process	2	73.9×	0.001	CRLF1, CLCF1
positive regulation of isotype switching to IgE isotypes	1	1404.3×	0.003	CLCF1
negative regulation of motor neuron apoptotic process	1	510.7×	0.005	CRLF1
positive regulation of astrocyte differentiation	1	468.1×	0.005	CLCF1
positive regulation of cell population proliferation	2	22.4×	0.006	CRLF1, CLCF1
positive regulation of immunoglobulin production	1	160.5×	0.011	CLCF1
ureteric bud development	1	151.8×	0.011	CRLF1
positive regulation of B cell proliferation	1	114.6×	0.013	CLCF1
cell surface receptor signaling pathway via JAK-STAT	1	96.8×	0.014	CLCF1
B cell differentiation	1	73.0×	0.017	CLCF1
cell surface receptor signaling pathway	1	21.4×	0.053	CLCF1
proteasome-mediated ubiquitin-dependent protein catabolic process	1	17.4×	0.060	KLHL7
protein ubiquitination	1	13.8×	0.071	KLHL7

Therapeutics

Drug target analysis

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

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
CRLF1	0	0
CLCF1	0	0
KLHL7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KLHL7	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CRLF1	1.1.1.105	all-trans-retinol dehydrogenase (NAD+)

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

0 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.

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	0
C	Druggable family + PDB, no drug	1	CRLF1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CLCF1, KLHL7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CRLF1	0	—
CLCF1	0	—
KLHL7	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.