PERCHING syndrome

Summary

PERCHING syndrome (MONDO:0014890) is a disease caused by KLHL7 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KLHL7 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	PERCHING syndrome
Mondo ID	MONDO:0014890
OMIM	617055
Orphanet	603684
DOID	DOID:0080331
UMLS	C4310742
MedGen	934709
GARD	0018278
Is cancer (heuristic)	no

Also known as: CISS3 · cold-induced sweating syndrome caused by mutation in KLHL7 · cold-induced sweating syndrome type 3 · CRISPONI/cold-induced sweating syndrome 3 · Crisponi/cold-induced sweating syndrome 3 · KLHL7 cold-induced sweating syndrome · KLHL7-related bohring-opitz-like/cold-induced sweating-like overlap syndrome · PERCHING

Data availability: 27 ClinVar variants · 4 GenCC gene-disease records.

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 › PERCHING syndrome

Related subtypes (2): Cold-induced sweating syndrome 1, cold-induced sweating syndrome 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

ClinVar germline variants

27 retrieved; paginated sample, class counts are floors:

8 pathogenic, 8 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 uncertain significance, 3 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030980	NM_001031710.3(KLHL7):c.807C>A (p.Tyr269Ter)	KLHL7	Pathogenic	criteria provided, single submitter
1228383	NM_001031710.3(KLHL7):c.1114C>T (p.Arg372Ter)	KLHL7	Pathogenic	criteria provided, single submitter
1527856	NM_001031710.3(KLHL7):c.642G>C (p.Trp214Cys)	KLHL7	Pathogenic	no assertion criteria provided
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
691635	NM_001031710.3(KLHL7):c.249del (p.Phe83fs)	KLHL7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804273	NM_001031710.3(KLHL7):c.1051C>T (p.Arg351Ter)	KLHL7	Pathogenic	criteria provided, multiple submitters, no conflicts
816804	NM_001031710.3(KLHL7):c.565C>T (p.Arg189Ter)	KLHL7	Pathogenic	criteria provided, multiple submitters, no conflicts
1228387	NM_001031710.3(KLHL7):c.223+5G>C	KLHL7	Likely pathogenic	criteria provided, single submitter
1228389	NM_001031710.3(KLHL7):c.815T>C (p.Leu272Pro)	KLHL7	Likely pathogenic	criteria provided, single submitter
1341505	NM_001031710.3(KLHL7):c.944del (p.Ser315fs)	KLHL7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2584468	NM_001031710.3(KLHL7):c.569dup (p.Thr191fs)	KLHL7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2584469	NM_001031710.3(KLHL7):c.576TCT[1] (p.Leu194del)	KLHL7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2920712	NM_001031710.3(KLHL7):c.619-349A>G	KLHL7	Likely pathogenic	criteria provided, single submitter
4532064	NM_001031710.3(KLHL7):c.776G>A (p.Cys259Tyr)	KLHL7	Likely pathogenic	criteria provided, single submitter
487514	NM_001031710.3(KLHL7):c.618+1G>A	KLHL7	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
279824	NM_001031710.3(KLHL7):c.976C>T (p.Arg326Ter)	KLHL7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
430626	NM_001031710.3(KLHL7):c.178GTT[1] (p.Val61del)	KLHL7	Conflicting classifications of pathogenicity	no assertion criteria provided
452804	NM_001031710.3(KLHL7):c.793+5G>C	KLHL7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3024162	NM_001031710.3(KLHL7):c.254T>G (p.Val85Gly)	KLHL7	Uncertain significance	no assertion criteria provided
3064762	NM_001031710.3(KLHL7):c.317+4A>G	KLHL7	Uncertain significance	criteria provided, single submitter
3376595	NM_001031710.3(KLHL7):c.1463G>A (p.Gly488Asp)	KLHL7	Uncertain significance	criteria provided, single submitter
359798	NM_001031710.3(KLHL7):c.352C>T (p.Leu118=)	KLHL7	Benign	criteria provided, multiple submitters, no conflicts
802301	NM_001031710.3(KLHL7):c.121-5814A>G	KLHL7	Benign	criteria provided, single submitter
802302	NM_001031710.3(KLHL7):c.936+3731_936+3735del	KLHL7	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
KLHL7	Definitive	Autosomal recessive	PERCHING syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KLHL7	HGNC:15646	ENSG00000122550	Q8IXQ5	Kelch-like protein 7	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KLHL7	Kelch-like protein 7	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.

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)
KLHL7	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KLHL7	274	ubiquitous	marker	oocyte, secondary oocyte, heart right ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KLHL7	1,123

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KLHL7	Q8IXQ5	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.024	KLHL7
protein ubiquitination	1	41.4×	0.024	KLHL7

Therapeutics

Drug target analysis

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

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
KLHL7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KLHL7	1	Binding:1

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KLHL7

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)
KLHL7	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.