Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

Summary

Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (MONDO:0014089) is a disease caused by NLRP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NLRP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome
Mondo ID	MONDO:0014089
OMIM	615225, 616964
Orphanet	352662
UMLS	C3808876
MedGen	815206
GARD	0017525
Is cancer (heuristic)	no

Also known as: CIDED · corneal intraepithelial dyskeratosis and ectodermal dysplasia · MSPC · palmoplantar carcinoma, multiple self-healing · palmoplantar carcinoma, multiple self-healing; MSPC

Data availability: 25 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › diffuse palmoplantar keratoderma › corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

Related subtypes (31): autosomal dominant palmoplantar keratoderma and congenital alopecia, dermatopathia pigmentosa reticularis, Clouston syndrome, epidermolytic palmoplantar keratoderma, 1, palmoplantar keratoderma-deafness syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, keratosis palmaris et plantaris-clinodactyly syndrome, Bart-Pumphrey syndrome, Naegeli-Franceschetti-Jadassohn syndrome, palmoplantar keratoderma-sclerodactyly syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, Schöpf-Schulz-Passarge syndrome, hereditary palmoplantar keratoderma, Gamborg-Nielsen type, Papillon-Lefevre disease, Haim-Munk syndrome, mal de Meleda, odonto-onycho-dermal dysplasia, palmoplantar keratoderma, Bothnian type, diffuse nonepidermolytic palmoplantar keratoderma, loricrin keratoderma, skin fragility-woolly hair-palmoplantar keratoderma syndrome, Curly hair - acral keratoderma - caries syndrome, CEDNIK syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, palmoplantar keratoderma, Nagashima type, erythrokeratodermia variabilis, diffuse palmoplantar keratoderma with painful fissures, KID syndrome, diffuse palmoplantar keratoderma - acrocyanosis syndrome, hearing loss with skin disease

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

25 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 4 benign/likely benign, 3 pathogenic, 2 likely benign, 1 likely pathogenic, 1 benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
375413	NM_033004.4(NLRP1):c.160G>A (p.Ala54Thr)	NLRP1	Pathogenic	criteria provided, single submitter
393318	NM_001033053.2(NLRP1):c.2358-?_2528+?del	NLRP1	Pathogenic	no assertion criteria provided
50316	NM_033004.4(NLRP1):c.230T>C (p.Met77Thr)	NLRP1	Pathogenic	no assertion criteria provided
375414	NM_033004.4(NLRP1):c.197C>T (p.Ala66Val)	NLRP1	Likely pathogenic	criteria provided, single submitter
714854	NM_033004.4(NLRP1):c.2841G>C (p.Arg947Ser)	NLRP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016715	NM_033004.4(NLRP1):c.439C>T (p.Arg147Cys)	NLRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1366760	NM_033004.4(NLRP1):c.164C>T (p.Ser55Leu)	NLRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1369278	NM_033004.4(NLRP1):c.4097G>A (p.Arg1366His)	NLRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1441287	NM_033004.4(NLRP1):c.3338C>T (p.Thr1113Met)	NLRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1442888	NM_033004.4(NLRP1):c.1040T>G (p.Val347Gly)	NLRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1481802	NM_033004.4(NLRP1):c.2528+1G>C	NLRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1502179	NM_033004.4(NLRP1):c.2043G>T (p.Glu681Asp)	NLRP1	Uncertain significance	criteria provided, single submitter
1512598	NM_033004.4(NLRP1):c.2870+1G>A	NLRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
225421	NM_033004.4(NLRP1):c.922C>T (p.Arg308Ter)	NLRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068085	NM_033004.4(NLRP1):c.4399_4404del (p.Gly1467_Leu1468del)	NLRP1	Uncertain significance	criteria provided, single submitter
3582339	NM_033004.4(NLRP1):c.2960G>A (p.Arg987Gln)	NLRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4278358	NM_033004.4(NLRP1):c.2675_2686del (p.Pro892_Lys895del)	NLRP1	Uncertain significance	criteria provided, single submitter
803299	NM_033004.4(NLRP1):c.4181C>A (p.Thr1394Lys)	NLRP1	Uncertain significance	criteria provided, single submitter
1097101	NM_033004.4(NLRP1):c.3228C>T (p.Asp1076=)	NLRP1	Likely benign	criteria provided, multiple submitters, no conflicts
403240	NM_033004.4(NLRP1):c.3550A>G (p.Met1184Val)	NLRP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
403241	NM_033004.4(NLRP1):c.114G>C (p.Ser38=)	NLRP1	Benign	criteria provided, multiple submitters, no conflicts
4163	NM_033004.4(NLRP1):c.464T>A (p.Leu155His)	NLRP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
734173	NM_033004.4(NLRP1):c.272-7C>G	NLRP1	Likely benign	criteria provided, multiple submitters, no conflicts
770795	NM_033004.4(NLRP1):c.316G>A (p.Gly106Arg)	NLRP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
808209	NM_033004.4(NLRP1):c.923G>A (p.Arg308Gln)	NLRP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 1 · 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
NLRP1	Strong	Autosomal dominant	corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NLRP1	Orphanet:352662	Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis 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
NLRP1	HGNC:14374	ENSG00000091592	Q9C000	NACHT, LRR and PYD domains-containing protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NLRP1	NACHT, LRR and PYD domains-containing protein 1	Acts as the sensor component of the NLRP1 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis.

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)
NLRP1	Other/Unknown	no		CARD, Leu-rich_rpt, DAPIN

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
granulocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLRP1	203	ubiquitous	marker	granulocyte, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NLRP1	1,544

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NLRP1	Q9C000	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
The NLRP1 inflammasome	1	3806.7×	3e-04	NLRP1

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
NLRP1 inflammasome complex assembly	1	16852.0×	0.001	NLRP1
self proteolysis	1	1532.0×	0.004	NLRP1
response to muramyl dipeptide	1	1404.3×	0.004	NLRP1
cellular response to UV-B	1	1404.3×	0.004	NLRP1
pattern recognition receptor signaling pathway	1	991.3×	0.004	NLRP1
pyroptotic inflammatory response	1	510.7×	0.006	NLRP1
activation of innate immune response	1	481.5×	0.006	NLRP1
intrinsic apoptotic signaling pathway	1	358.6×	0.007	NLRP1
positive regulation of interleukin-1 beta production	1	259.3×	0.009	NLRP1
antiviral innate immune response	1	227.7×	0.009	NLRP1
neuron apoptotic process	1	185.2×	0.010	NLRP1
regulation of inflammatory response	1	168.5×	0.010	NLRP1
positive regulation of inflammatory response	1	145.3×	0.011	NLRP1
protein homooligomerization	1	122.1×	0.012	NLRP1
defense response to bacterium	1	108.0×	0.012	NLRP1
regulation of apoptotic process	1	83.4×	0.015	NLRP1
defense response to virus	1	69.3×	0.017	NLRP1
inflammatory response	1	37.7×	0.029	NLRP1
apoptotic process	1	28.7×	0.037	NLRP1
signal transduction	1	16.1×	0.062	NLRP1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

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
NLRP1	PERHEXILINE MALEATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NLRP1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PERHEXILINE MALEATE	4	NLRP1
DITHIAZANINE IODIDE	4	NLRP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NLRP1	2	Functional: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

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)
PERHEXILINE MALEATE	4	NLRP1
DITHIAZANINE IODIDE	4	NLRP1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NLRP1
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	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.