Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Summary

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (MONDO:0011581) is a disease caused by DSP (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DSP (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 4,569
• Phenotypes (HPO): 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

4 HPO clinical features (Orphanet curated; top 4 by frequency):

HPO ID	Term	Frequency
HP:0001644	Dilated cardiomyopathy	Very frequent (80-99%)
HP:0002224	Woolly hair	Very frequent (80-99%)
HP:0005588	Patchy palmoplantar keratoderma	Very frequent (80-99%)
HP:0001635	Congestive heart failure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Mondo ID	MONDO:0011581
MeSH	C535581
OMIM	605676
Orphanet	65282
DOID	DOID:0090128
SNOMED CT	719835006
UMLS	C1854063
MedGen	340124
GARD	0005595
Is cancer (heuristic)	no

Also known as: arrhythmogenic cardiomyopathy with wooly hair and keratoderma · cardiomyopathy dilated with woolly hair and keratoderma · cardiomyopathy dilated with wooly hair and keratoderma · cardiomyopathy, dilated, with woolly hair and keratoderma · cardiomyopathy, dilated, with wooly hair and keratoderma · Carvajal syndrome · DCWHK · dilated cardiomyopathy with wooly hair and keratoderma · epidermolytic palmoplantar keratoderma woolly hair and dilated cardiomyopathy · epidermolytic palmoplantar keratoderma wooly hair and dilated cardiomyopathy · keratoderma with woolly hair type II · keratoderma with wooly hair type II · KWWH type II · palmoplantar keratoderma with left ventricular cardiomyopathy and woolly hair · palmoplantar keratoderma with left ventricular cardiomyopathy and wooly hair · woolly hair - palmoplantar keratoderma - dilated cardiomyopathy · woolly hair - palmoplantar keratoderma - dilated cardiomyopathy syndrome · woolly hair-palmoplantar hyperkeratosis-dilated cardiomyopathy syndrome · woolly hair-palmoplantar keratoderma-dilated cardiomyopathy syndrome · wooly hair - palmoplantar keratoderma - dilated cardiomyopathy (+3 more)

Data availability: 4,569 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › ectodermal dysplasia syndrome › arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Related subtypes (119): ADULT syndrome, autosomal dominant palmoplantar keratoderma and congenital alopecia, ameloonychohypohidrotic syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, anonychia with flexural pigmentation, Böök syndrome, blepharocheilodontic syndrome, Stern-Lubinsky-Durrie syndrome, dermatopathia pigmentosa reticularis, dermo-odonto dysplasia, Rapp-Hodgkin syndrome, Clouston syndrome, ectodermal dysplasia, trichoodontoonychial type, gingival fibromatosis-hypertrichosis syndrome, hypertrichosis cubiti-short stature syndrome, Johnson neuroectodermal syndrome, Marshall syndrome, Naegeli-Franceschetti-Jadassohn syndrome, oculodentodigital dysplasia, Cronkhite-Canada syndrome, scalp-ear-nipple syndrome, tooth and nail syndrome, tricho-dento-osseous syndrome, tricho-retino-dento-digital syndrome, acrofacial dysostosis, Weyers type, Ackerman syndrome, alopecia - contractures - dwarfism - intellectual disability syndrome, AREDYLD syndrome, Barber-Say syndrome, oculoosteocutaneous syndrome, cataract-hypertrichosis-intellectual disability syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, cerebellar ataxia-ectodermal dysplasia syndrome, cranioectodermal dysplasia, conductive deafness-ptosis-skeletal anomalies syndrome, dermatoosteolysis, Kirghizian type, Dubowitz syndrome, ectodermal dysplasia-sensorineural deafness syndrome, ectodermal dysplasia-intellectual disability-central nervous system malformation syndrome, hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome, cleft lip/palate-ectodermal dysplasia syndrome, EEM syndrome, Ellis-van Creveld syndrome, amelocerebrohypohidrotic syndrome, GAPO syndrome, ichthyosis-alopecia-eclabion-ectropion-intellectual disability syndrome, Leukomelanoderma-infantilism-intellectual disability-hypodontia-hypotrichosis syndrome, Dahlberg-Borer-Newcomer syndrome, cartilage-hair hypoplasia, oculotrichodysplasia, pilodental dysplasia-refractive errors syndrome, Bartsocas-Papas syndrome 1, ectodermal dysplasia-blindness syndrome, Schinzel-Giedion syndrome, Teebi-Shaltout syndrome, taurodontia-absent teeth-sparse hair syndrome, odontotrichomelic syndrome, trichomegaly-retina pigmentary degeneration-dwarfism syndrome, trichoodontoonychial dysplasia, CHIME syndrome, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, Ito hypomelanosis, contractures-ectodermal dysplasia-cleft lip/palate syndrome, incontinentia pigmenti, Toriello-Lacassie-Droste syndrome, odontomicronychial dysplasia, ectodermal dysplasia with natal teeth, Turnpenny type, hidrotic ectodermal dysplasia, Christianson-Fourie type, trichodental syndrome, congenital hypotrichosis with juvenile macular dystrophy, tricho-oculo-dermo-vertebral syndrome, odonto-tricho-ungual-digito-palmar syndrome, Fried’s tooth and nail syndrome, limb-mammary syndrome, epidermolysis bullosa simplex due to plakophilin deficiency, Curly hair - acral keratoderma - caries syndrome, hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome, Lelis syndrome, Fontaine progeroid syndrome, ectodermal dysplasia-syndactyly syndrome, ectodermal dysplasia 5, hair/nail type, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, cardiofaciocutaneous syndrome, choroidal atrophy-alopecia syndrome, dyskeratosis congenita, hidrotic ectodermal dysplasia, Halal type, hypertrichosis lanuginosa congenita, hypohidrotic ectodermal dysplasia, odonto-onycho dysplasia-alopecia syndrome, pili torti-onychodysplasia syndrome, chondroectodermal dysplasia with night blindness, trichorhinophalangeal syndrome, trichothiodystrophy, trichodermodysplasia-dental alterations syndrome, autosomal dominant trichoodontoonychodysplasia-syndactyly, focal facial dermal dysplasia, KID syndrome, pure hair and nail ectodermal dysplasia, circumscribed palmoplantar hypokeratosis, trichodysplasia-amelogenesis imperfecta syndrome, dermotrichic syndrome, alves Castelo dos Santos syndrome, Brunoni syndrome, ectodermal dysplasia Bartalos type, ectodermal dysplasia margarita type, ectodermal dysplasia alopecia preaxial polydactyly, ectodermal dysplasia arthrogryposis diabetes mellitus, ectodermal dysplasia blindness, ectodermal dysplasia neurosensory deafness, ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, ectodermal dysplasia 15, hypohidrotic/hair type, linear hypopigmentation and craniofacial asymmetry with acral, ocular and brain anomalies, jones hersh yusk syndrome, ectodermal dysplasia 13, hair/tooth type, arthrogryposis-ectodermal dysplasia-other anomalies syndrome, ectodermal dysplasia WNT10A related, CTSC-related disorder, ectodermal dysplasia 17 with or without limb malformations

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

600 retrieved; paginated sample, class counts are floors:

257 uncertain significance, 139 likely benign, 96 pathogenic, 76 conflicting classifications of pathogenicity, 11 benign/likely benign, 11 likely pathogenic, 8 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012338	NM_004415.4(DSP):c.748C>T (p.Gln250Ter)	DSP	Pathogenic	criteria provided, single submitter
1034083	NM_004415.4(DSP):c.5664_5667del (p.Ser1888fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
1068839	NM_004415.4(DSP):c.2832del (p.Glu945fs)	DSP	Pathogenic	criteria provided, single submitter
1069300	NM_004415.4(DSP):c.3494dup (p.Glu1166fs)	DSP	Pathogenic	criteria provided, single submitter
1069527	NM_004415.4(DSP):c.4384_4387del (p.Glu1461_Ser1462insTer)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069659	NM_004415.4(DSP):c.1439del (p.Asp480fs)	DSP	Pathogenic	criteria provided, single submitter
1069787	NM_004415.4(DSP):c.4337_4338insTGCT (p.Gln1446fs)	DSP	Pathogenic	criteria provided, single submitter
1069816	NM_004415.4(DSP):c.7082dup (p.His2363fs)	DSP	Pathogenic	criteria provided, single submitter
1069979	NM_004415.4(DSP):c.2834_2835del (p.Glu945fs)	DSP	Pathogenic	criteria provided, single submitter
1070194	NM_004415.4(DSP):c.4882del (p.Arg1628fs)	DSP	Pathogenic	criteria provided, single submitter
1070495	NM_004415.4(DSP):c.5671_5674del (p.Glu1891fs)	DSP	Pathogenic	criteria provided, single submitter
1070496	NM_004415.4(DSP):c.6562del (p.Glu2188fs)	DSP	Pathogenic	criteria provided, single submitter
1070590	NM_004415.4(DSP):c.4201G>T (p.Glu1401Ter)	DSP	Pathogenic	criteria provided, single submitter
1071031	NM_004415.4(DSP):c.5806C>T (p.Gln1936Ter)	DSP	Pathogenic	criteria provided, single submitter
1071053	NM_004415.4(DSP):c.1339C>T (p.Gln447Ter)	DSP	Pathogenic	criteria provided, single submitter
1071328	NM_004415.4(DSP):c.3465G>A (p.Trp1155Ter)	DSP	Pathogenic	criteria provided, single submitter
1071932	NM_004415.4(DSP):c.4434dup (p.Lys1479Ter)	DSP	Pathogenic	criteria provided, single submitter
1072004	NM_004415.4(DSP):c.5014C>T (p.Gln1672Ter)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
1072032	NM_004415.4(DSP):c.3338del (p.Arg1113fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
1072033	NM_004415.4(DSP):c.1656C>G (p.Tyr552Ter)	DSP	Pathogenic	criteria provided, single submitter
1072294	NM_004415.4(DSP):c.2655del (p.Lys886fs)	DSP	Pathogenic	criteria provided, single submitter
1072470	NM_004415.4(DSP):c.4687_4688del (p.Leu1563fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072769	NM_004415.4(DSP):c.1186del (p.Gln396fs)	DSP	Pathogenic	criteria provided, single submitter
1073737	NM_004415.4(DSP):c.894G>A (p.Trp298Ter)	DSP	Pathogenic	criteria provided, single submitter
1073940	NM_004415.4(DSP):c.2903dup (p.Tyr968Ter)	DSP	Pathogenic	criteria provided, single submitter
1074224	NM_004415.4(DSP):c.2223T>G (p.Tyr741Ter)	DSP	Pathogenic	criteria provided, single submitter
1074954	NM_004415.4(DSP):c.3045del (p.Arg1015fs)	DSP	Pathogenic	criteria provided, single submitter
1074955	NM_004415.4(DSP):c.3535C>T (p.Gln1179Ter)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
1075135	NM_004415.4(DSP):c.2185dup (p.Met729fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
1075169	NM_004415.4(DSP):c.3094del (p.Thr1032fs)	DSP	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 11 · 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
DSP	Definitive	Autosomal dominant	arrhythmogenic cardiomyopathy with wooly hair and keratoderma	26

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSP	Orphanet:154	Familial isolated dilated cardiomyopathy
DSP	Orphanet:158687	Lethal acantholytic erosive disorder
DSP	Orphanet:2032	Idiopathic pulmonary fibrosis
DSP	Orphanet:293165	Skin fragility-woolly hair-palmoplantar keratoderma syndrome
DSP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSP	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSP	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSP	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSP	Orphanet:476096	Erythrokeratodermia-cardiomyopathy syndrome
DSP	Orphanet:50942	Striate palmoplantar keratoderma
DSP	Orphanet:65282	Carvajal syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	gencc,clinvar
SNRNP48	HGNC:21368	ENSG00000168566	Q6IEG0	U11/U12 small nuclear ribonucleoprotein 48 kDa protein	clinvar
DSP-AS1	HGNC:56039	ENSG00000261189		DSP antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSP	Desmoplakin	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
SNRNP48	U11/U12 small nuclear ribonucleoprotein 48 kDa protein	Likely involved in U12-type 5’ splice site recognition.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	1	5.8×	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)
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
SNRNP48	Transcription factor	no		TRM13/UPF0224_CHHC_Znf_dom, Znf_C2H2_sf, UPF0224_FAM112_RNA_Proc
DSP-AS1	Other/Unknown	no

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
hair follicle	1
skin of hip	1
upper leg skin	1
buccal mucosa cell	1
calcaneal tendon	1
tendon	1
apex of heart	1
male germ line stem cell (sensu Vertebrata) in testis	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
SNRNP48	244	ubiquitous	yes	buccal mucosa cell, tendon, calcaneal tendon
DSP-AS1	162		marker	male germ line stem cell (sensu Vertebrata) in testis, apex of heart, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DSP	2,897
SNRNP48	1,528
DSP-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SNRNP48	Q6IEG0	7
DSP	P15924	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Apoptotic cleavage of cell adhesion proteins	1	519.1×	0.019	DSP
RND1 GTPase cycle	1	132.8×	0.022	DSP
RND3 GTPase cycle	1	129.8×	0.022	DSP
mRNA Splicing - Minor Pathway	1	112.0×	0.022	SNRNP48
mRNA Splicing	1	54.9×	0.035	SNRNP48
Formation of the cornified envelope	1	43.9×	0.035	DSP
Processing of Capped Intron-Containing Pre-mRNA	1	41.1×	0.035	SNRNP48
Keratinization	1	27.9×	0.044	DSP
Metabolism of RNA	1	20.8×	0.053	SNRNP48
Neutrophil degranulation	1	11.5×	0.085	DSP

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ventricular compact myocardium morphogenesis	1	1203.7×	0.004	DSP
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	1	1203.7×	0.004	DSP
desmosome organization	1	1053.2×	0.004	DSP
protein localization to cell-cell junction	1	936.2×	0.004	DSP
peptide cross-linking	1	702.2×	0.004	DSP
regulation of ventricular cardiac muscle cell action potential	1	702.2×	0.004	DSP
epithelial cell-cell adhesion	1	601.9×	0.004	DSP
intermediate filament cytoskeleton organization	1	468.1×	0.005	DSP
adherens junction organization	1	255.3×	0.008	DSP
skin development	1	221.7×	0.008	DSP
regulation of heart rate by cardiac conduction	1	187.2×	0.009	DSP
keratinocyte differentiation	1	123.9×	0.011	DSP
intermediate filament organization	1	120.4×	0.011	DSP
wound healing	1	113.9×	0.011	DSP
epidermis development	1	105.3×	0.011	DSP
cell-cell adhesion	1	50.8×	0.022	DSP
RNA splicing	1	44.1×	0.024	SNRNP48
mRNA processing	1	39.4×	0.025	SNRNP48

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
DSP	0	0
SNRNP48	0	0
DSP-AS1	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
DSP	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	3	DSP, SNRNP48, DSP-AS1

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)
DSP	2	—
SNRNP48	0	—
DSP-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.