Arrhythmogenic right ventricular dysplasia 8

Summary

Arrhythmogenic right ventricular dysplasia 8 (MONDO:0011831) is a disease caused by DSP (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: DSP (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 4,110

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arrhythmogenic right ventricular dysplasia 8
Mondo ID	MONDO:0011831
MeSH	C564400
OMIM	607450
DOID	DOID:0110076
UMLS	C1843896
MedGen	336069
GARD	0024825
Is cancer (heuristic)	no

Also known as: arrhythmogenic right ventricular cardiomyopathy 8 · arrhythmogenic right ventricular cardiomyopathy caused by mutation in DSP · arrhythmogenic right ventricular dysplasia 8 · arrhythmogenic right ventricular dysplasia type 8 · arrhythmogenic right ventricular dysplasia, familial, 8 · arrhythmogenic right ventricular dysplasia, familial, type 8 · ARVC8 · ARVD8 · DSP arrhythmogenic right ventricular cardiomyopathy

Data availability: 4,110 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › familial cardiomyopathy › familial isolated arrhythmogenic right ventricular dysplasia › arrhythmogenic right ventricular dysplasia 8

Related subtypes (15): arrhythmogenic right ventricular dysplasia 13, arrhythmogenic right ventricular dysplasia 1, arrhythmogenic right ventricular dysplasia 3, arrhythmogenic right ventricular dysplasia 4, arrhythmogenic right ventricular dysplasia 5, arrhythmogenic right ventricular dysplasia 6, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 9, arrhythmogenic right ventricular dysplasia 10, arrhythmogenic right ventricular dysplasia 11, arrhythmogenic right ventricular dysplasia 12, familial isolated arrhythmogenic ventricular dysplasia, left dominant form, familial isolated arrhythmogenic ventricular dysplasia, biventricular form, familial isolated arrhythmogenic ventricular dysplasia, right dominant form, arrhythmogenic right ventricular dysplasia, familial, 14

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:

255 uncertain significance, 137 likely benign, 96 pathogenic, 80 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: 14 · 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
TUBB3	Orphanet:300570	Cortical dysgenesis with pontocerebellar hypoplasia due to TUBB3 mutation
TUBB3	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBB3	Orphanet:467166	Tubulinopathy-associated dysgyria

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	gencc,clinvar
TUBB3	HGNC:20772	ENSG00000258947	Q13509	Tubulin beta-3 chain	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.
TUBB3	Tubulin beta-3 chain	Tubulin is the major constituent of microtubules, protein filaments consisting of alpha- and beta-tubulin heterodimers.
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: 2 · 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	4.3×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
TUBB3	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
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.

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hair follicle	1
skin of hip	1
upper leg skin	1
cortical plate	1
embryo	1
ganglionic eminence	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
TUBB3	144	ubiquitous	marker	cortical plate, ganglionic eminence, embryo
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: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB3	6,797
DSP	2,897
SNRNP48	1,528
DSP-AS1	0

Intra-cohort edges

A	B	Sources
DSP	TUBB3	intact

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TUBB3	Q13509	28
SNRNP48	Q6IEG0	7
DSP	P15924	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 96. Enrichment computed across 4 evidence-associated genes (3 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 3 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	346.1×	0.046	DSP
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	181.3×	0.046	TUBB3
Transport of connexons to the plasma membrane	1	181.3×	0.046	TUBB3
Gap junction trafficking and regulation	1	158.6×	0.046	TUBB3
Gap junction trafficking	1	158.6×	0.046	TUBB3
Post-chaperonin tubulin folding pathway	1	158.6×	0.046	TUBB3
Formation of tubulin folding intermediates by CCT/TriC	1	141.0×	0.046	TUBB3
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	135.9×	0.046	TUBB3
Prefoldin mediated transfer of substrate to CCT/TriC	1	131.3×	0.046	TUBB3
Activation of AMPK downstream of NMDARs	1	126.9×	0.046	TUBB3
RHO GTPases activate IQGAPs	1	115.3×	0.046	TUBB3
Sealing of the nuclear envelope (NE) by ESCRT-III	1	115.3×	0.046	TUBB3
HCMV Infection	1	108.8×	0.046	TUBB3
Chaperonin-mediated protein folding	1	100.2×	0.046	TUBB3
Gap junction assembly	1	97.6×	0.046	TUBB3
Nuclear Envelope (NE) Reassembly	1	97.6×	0.046	TUBB3
Selective autophagy	1	92.8×	0.046	TUBB3
RND1 GTPase cycle	1	88.5×	0.046	DSP
Protein folding	1	86.5×	0.046	TUBB3
RND3 GTPase cycle	1	86.5×	0.046	DSP
Assembly and cell surface presentation of NMDA receptors	1	84.6×	0.046	TUBB3
Cargo trafficking to the periciliary membrane	1	82.8×	0.046	TUBB3
Aggrephagy	1	82.8×	0.046	TUBB3
Carboxyterminal post-translational modifications of tubulin	1	79.3×	0.046	TUBB3
Recycling pathway of L1	1	74.6×	0.046	TUBB3
mRNA Splicing - Minor Pathway	1	74.6×	0.046	SNRNP48
COPI-independent Golgi-to-ER retrograde traffic	1	69.2×	0.046	TUBB3
Post NMDA receptor activation events	1	68.0×	0.046	TUBB3
Intraflagellar transport	1	66.8×	0.046	TUBB3
Antimicrobial mechanism of IFN-stimulated genes	1	65.6×	0.046	TUBB3

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
dorsal root ganglion development	1	1123.5×	0.007	TUBB3
ventricular compact myocardium morphogenesis	1	802.5×	0.007	DSP
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	1	802.5×	0.007	DSP
desmosome organization	1	702.2×	0.007	DSP
protein localization to cell-cell junction	1	624.1×	0.007	DSP
peptide cross-linking	1	468.1×	0.007	DSP
regulation of ventricular cardiac muscle cell action potential	1	468.1×	0.007	DSP
epithelial cell-cell adhesion	1	401.2×	0.007	DSP
intermediate filament cytoskeleton organization	1	312.1×	0.008	DSP
adherens junction organization	1	170.2×	0.013	DSP
skin development	1	147.8×	0.013	DSP
regulation of heart rate by cardiac conduction	1	124.8×	0.015	DSP
keratinocyte differentiation	1	82.6×	0.019	DSP
intermediate filament organization	1	80.2×	0.019	DSP
wound healing	1	75.9×	0.019	DSP
epidermis development	1	70.2×	0.019	DSP
mitotic cell cycle	1	44.6×	0.029	TUBB3
microtubule cytoskeleton organization	1	40.4×	0.030	TUBB3
cell-cell adhesion	1	33.8×	0.034	DSP
axon guidance	1	30.2×	0.035	TUBB3
RNA splicing	1	29.4×	0.035	SNRNP48
mRNA processing	1	26.2×	0.038	SNRNP48

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
TUBB3	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB3	21	4
DSP	0	0
SNRNP48	0	0
DSP-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB3
VINBLASTINE	4	TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBB3
DOCETAXEL	4	TUBB3
NOSCAPINE	4	TUBB3
VINBLASTINE SULFATE	4	TUBB3
PACLITAXEL	4	TUBB3
LEVOFLOXACIN	4	TUBB3
VINORELBINE	4	TUBB3
TIRBANIBULIN	4	TUBB3
PODOFILOX	4	TUBB3
VINCRISTINE	4	TUBB3
DOCETAXEL ANHYDROUS	4	TUBB3
PATUPILONE	3	TUBB3
ABT-751	2	TUBB3
MAYTANSINE	2	TUBB3
DOLASTATIN-10	2	TUBB3
INDIBULIN	2	TUBB3
PARBENDAZOLE	2	TUBB3
NOCODAZOLE	2	TUBB3
COMBRETASTATIN	1	TUBB3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBB3	1,781	Binding:1741, Functional:34, ADMET:6
DSP	2	Binding:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TUBB3	1,781

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

21 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)
COLCHICINE	4	TUBB3
VINBLASTINE	4	TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBB3
DOCETAXEL	4	TUBB3
NOSCAPINE	4	TUBB3
VINBLASTINE SULFATE	4	TUBB3
PACLITAXEL	4	TUBB3
LEVOFLOXACIN	4	TUBB3
VINORELBINE	4	TUBB3
TIRBANIBULIN	4	TUBB3
PODOFILOX	4	TUBB3
VINCRISTINE	4	TUBB3
DOCETAXEL ANHYDROUS	4	TUBB3
PATUPILONE	3	TUBB3
ABT-751	2	TUBB3
MAYTANSINE	2	TUBB3
DOLASTATIN-10	2	TUBB3
INDIBULIN	2	TUBB3
PARBENDAZOLE	2	TUBB3
NOCODAZOLE	2	TUBB3
COMBRETASTATIN	1	TUBB3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB3
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.