DSP

desmoplakin, the group of Plakins

Basic information

Region (hg38): 6:7541616-7586714

Links

ENSG00000096696 ∙ NCBI:1832 ∙ OMIM:125647 ∙ HGNC:3052 ∙ Uniprot:P15924 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• keratosis palmoplantaris striata 2 (Strong), mode of inheritance: AD
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (Strong), mode of inheritance: AD
• lethal acantholytic epidermolysis bullosa (Strong), mode of inheritance: AR
• skin fragility-woolly hair-palmoplantar keratoderma syndrome (Strong), mode of inheritance: AR
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma (Strong), mode of inheritance: AR
• lethal acantholytic epidermolysis bullosa (Moderate), mode of inheritance: AR
• lethal acantholytic epidermolysis bullosa (Strong), mode of inheritance: AR
• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• striate palmoplantar keratoderma (Supportive), mode of inheritance: AD
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma (Supportive), mode of inheritance: AD
• lethal acantholytic epidermolysis bullosa (Supportive), mode of inheritance: AR
• skin fragility-woolly hair-palmoplantar keratoderma syndrome (Supportive), mode of inheritance: AD
• severe dermatitis-multiple allergies-metabolic wasting syndrome (Supportive), mode of inheritance: AR
• skin fragility-woolly hair-palmoplantar keratoderma syndrome (Limited), mode of inheritance: AR
• keratosis palmoplantaris striata 2 (Limited), mode of inheritance: AD
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma (Moderate), mode of inheritance: AR
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (Moderate), mode of inheritance: AD
• arrhythmogenic right ventricular dysplasia 8 (Definitive), mode of inheritance: AD
• arrhythmogenic right ventricular dysplasia 8 (Definitive), mode of inheritance: AR
• arrhythmogenic right ventricular dysplasia 8 (Strong), mode of inheritance: AD
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma (Strong), mode of inheritance: AR
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (Strong), mode of inheritance: AD
• lethal acantholytic epidermolysis bullosa (Strong), mode of inheritance: AR
• hypertrophic cardiomyopathy (Disputed Evidence), mode of inheritance: AD
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Arrhythmogenic right ventricular dysplasia, familial 8; Cardiomyopathy, dilated, with wooly hair and keratoderma; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	AD/AR	Cardiovascular	Individuals may manifest with syncope, cardiac arrest, and sudden death, and surveillance may allow early diagnosis of sequelae; Preventive measures (eg, with antiarrhythmic pharmacologic agents and/or ICD placement) may be beneficial, though some individuals may require heart transplantation	Cardiovascular; Dermatologic	9738775; 9887343; 10902626; 11063735; 12373648; 11841538; 16175511; 16628197; 20940358; 21193976; 22527912; 22795705; 22949226
Homozygous/compound heterozygous variants reported as causing biventricular dilative cardiomyopathy with palmoplantar keratoderma and woolly hair (Skin fragility-woolly hair syndrome)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DSP gene.

• Cardiomyopathy (1677 variants)
• Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;Arrhythmogenic right ventricular dysplasia 8 (1646 variants)
• Cardiovascular phenotype (1181 variants)
• Arrhythmogenic right ventricular dysplasia 8;Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (942 variants)
• not provided (884 variants)
• not specified (433 variants)
• 6 conditions (249 variants)
• Arrhythmogenic right ventricular dysplasia 8 (230 variants)
• Woolly hair-skin fragility syndrome (204 variants)
• Lethal acantholytic epidermolysis bullosa (204 variants)
• Arrhythmogenic right ventricular cardiomyopathy (98 variants)
• Primary dilated cardiomyopathy (42 variants)
• Inborn genetic diseases (37 variants)
• Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (31 variants)
• Epidermolysis bullosa simplex due to plakophilin deficiency (26 variants)
• Keratosis palmoplantaris striata 2 (18 variants)
• Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (15 variants)
• Primary familial hypertrophic cardiomyopathy (14 variants)
• DSP-related condition (13 variants)
• Primary familial dilated cardiomyopathy (9 variants)
• Familial isolated arrhythmogenic right ventricular dysplasia (8 variants)
• Dilated cardiomyopathy 1A (7 variants)
• Long QT syndrome (6 variants)
• Primary dilated cardiomyopathy;Arrhythmogenic right ventricular cardiomyopathy (6 variants)
• Left ventricular noncompaction cardiomyopathy (6 variants)
• Arrhythmogenic right ventricular cardiomyopathy;Primary dilated cardiomyopathy (5 variants)
• Cardiac arrhythmia (5 variants)
• Cardiac arrest (4 variants)
• Arrhythmogenic cardiomyopathy (4 variants)
• Hypertrophic cardiomyopathy (4 variants)
• Ventricular tachycardia (4 variants)
• Dilated cardiomyopathy 1S (3 variants)
• Arrhythmogenic right ventricular dysplasia 9 (3 variants)
• DSP-Related Disorders (2 variants)
• Palmoplantar blistering;Skin fragility with non-scarring blistering (2 variants)
• Long QT syndrome;Primary dilated cardiomyopathy (2 variants)
• Arrhythmogenic right ventricular dysplasia 1 (2 variants)
• Myocarditis (2 variants)
• Conduction disorder of the heart (2 variants)
• Migraine;Primary dilated cardiomyopathy;Hemiplegia (1 variants)
• Ventricular tachycardia;Abnormal left ventricular function;Paroxysmal atrial fibrillation;Right ventricular dilatation;Syncope (1 variants)
• Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis;Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;Arrhythmogenic right ventricular dysplasia 8 (1 variants)
• Hypertrophic cardiomyopathy;Systolic heart failure (1 variants)
• Ventricular fibrillation (1 variants)
• Collapse (finding) (1 variants)
• Left ventricular noncompaction (1 variants)
• Arrhythmogenic right ventricular cardiomyopathy;Brugada syndrome (1 variants)
• Chronic obstructive pulmonary disease (1 variants)
• Restrictive cardiomyopathy;Long QT syndrome (1 variants)
• Brugada syndrome (1 variants)
• Progressive familial heart block (1 variants)
• Sudden death (1 variants)
• Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis;Arrhythmogenic right ventricular dysplasia 8;Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1 variants)
• Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;Arrhythmogenic right ventricular dysplasia 8;Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (1 variants)
• Primary dilated cardiomyopathy;Cardiomyopathy (1 variants)
• Chronic lung disease (1 variants)
• Subvalvular aortic stenosis (1 variants)
• Familial restrictive cardiomyopathy (1 variants)
• Catecholaminergic polymorphic ventricular tachycardia 1 (1 variants)
• Left ventricular hypertrophy (1 variants)
• Wolff-Parkinson-White pattern (1 variants)
• Ventricular arrhythmia;Right ventricular cardiomyopathy (1 variants)
• Long QT syndrome 1 (1 variants)
• Global developmental delay (1 variants)
• Ventricular fibrillation, paroxysmal familial, type 1 (1 variants)
• Restrictive cardiomyopathy (1 variants)
• Amyloidosis;Cardiomyopathy (1 variants)
• Left ventricular noncompaction cardiomyopathy;Ventricular tachycardia (1 variants)
• Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis;Arrhythmogenic right ventricular dysplasia 8 (1 variants)
• Sudden unexplained death;Arrhythmogenic right ventricular cardiomyopathy (1 variants)
• Right ventricular cardiomyopathy (1 variants)
• Combined pulmonary fibrosis-emphysema syndrome (1 variants)
• Marfanoid habitus and intellectual disability (1 variants)
• Hypertrophic cardiomyopathy;Cardiomyopathy;Long QT syndrome (1 variants)
• Interstitial lung disease 2 (1 variants)
• Sudden unexplained death (1 variants)
• Cardiac arrhythmia;Aortic dilatation;Bicuspid aortic valve;Ventricular fibrillation;Sudden cardiac death (1 variants)
• Hypertrophic cardiomyopathy;Cardiomyopathy (1 variants)
• DSP-related arrhythmogenic cardiomyopathy (1 variants)
• Paroxysmal familial ventricular fibrillation (1 variants)
• Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;Arrhythmogenic right ventricular cardiomyopathy;Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (1 variants)
• DSP-related cardiomyopathy (1 variants)
• Ventricular tachycardia;Long QT syndrome;Hypertrophic cardiomyopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DSP gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			9	854	16	879
missense	3	9	1547	101	4	1664
nonsense	111	62	5			178
start loss			1			1
frameshift	185	78	9			272
inframe indel		1	40	6		47
splice donor/acceptor (+/-2bp)	4	39	8	2		53
splice region			44	54	2	100
non coding			47	152	80	279
Total	303	189	1666	1115	100

Highest pathogenic variant AF is 0.0000263

Variants in DSP

This is a list of pathogenic ClinVar variants found in the DSP region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-7541635-C-T		Lethal acantholytic epidermolysis bullosa • Woolly hair-skin fragility syndrome • Epidermolysis bullosa simplex due to plakophilin deficiency • Arrhythmogenic right ventricular cardiomyopathy	Likely benign (Jun 14, 2016)
6-7541656-A-G		Woolly hair-skin fragility syndrome • Epidermolysis bullosa simplex due to plakophilin deficiency • Arrhythmogenic right ventricular cardiomyopathy • Lethal acantholytic epidermolysis bullosa	Uncertain significance (Jun 14, 2016)
6-7541688-C-A		Epidermolysis bullosa simplex due to plakophilin deficiency • Arrhythmogenic right ventricular cardiomyopathy • Woolly hair-skin fragility syndrome • Lethal acantholytic epidermolysis bullosa	Uncertain significance (Jun 14, 2016)
6-7541726-G-T		Arrhythmogenic right ventricular cardiomyopathy • Lethal acantholytic epidermolysis bullosa • Woolly hair-skin fragility syndrome • Epidermolysis bullosa simplex due to plakophilin deficiency	Uncertain significance (Jun 14, 2016)
6-7541737-T-C		Woolly hair-skin fragility syndrome • Arrhythmogenic right ventricular cardiomyopathy • Epidermolysis bullosa simplex due to plakophilin deficiency • Lethal acantholytic epidermolysis bullosa	Uncertain significance (Jun 14, 2016)
6-7541759-G-A		Lethal acantholytic epidermolysis bullosa • Woolly hair-skin fragility syndrome • Arrhythmogenic right ventricular dysplasia 8 • 6 conditions	Uncertain significance (Sep 03, 2021)
6-7541812-G-A		Woolly hair-skin fragility syndrome • Arrhythmogenic right ventricular dysplasia 8 • Lethal acantholytic epidermolysis bullosa	Uncertain significance (Jan 30, 2019)
6-7541840-C-T		Lethal acantholytic epidermolysis bullosa • Woolly hair-skin fragility syndrome • Arrhythmogenic right ventricular dysplasia 8	Uncertain significance (Jan 12, 2018)
6-7541846-C-T		Woolly hair-skin fragility syndrome • Lethal acantholytic epidermolysis bullosa • Arrhythmogenic right ventricular dysplasia 8 • 6 conditions	Uncertain significance (Aug 10, 2021)
6-7541872-G-A		not specified	Likely benign (Sep 01, 2017)
6-7541880-C-A		Arrhythmogenic right ventricular cardiomyopathy • Epidermolysis bullosa simplex due to plakophilin deficiency • Woolly hair-skin fragility syndrome • Lethal acantholytic epidermolysis bullosa	Uncertain significance (Jun 14, 2016)
6-7541882-C-T			Benign (Mar 03, 2015)
6-7541884-G-T			Likely benign (Apr 12, 2018)
6-7541901-C-T		Cardiomyopathy	Uncertain significance (Nov 08, 2023)
6-7541909-C-T		Cardiomyopathy	Uncertain significance (Aug 31, 2023)
6-7541914-AC-GCA		Cardiovascular phenotype	Uncertain significance (Feb 21, 2018)
6-7541915-C-CA		not specified • Arrhythmogenic right ventricular cardiomyopathy • Lethal acantholytic epidermolysis bullosa • Woolly hair-skin fragility syndrome • Cardiovascular phenotype • Cardiomyopathy • Arrhythmogenic right ventricular dysplasia 8	Conflicting classifications of pathogenicity (Sep 23, 2022)
6-7541916-A-G		Cardiomyopathy • Cardiovascular phenotype • Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	Conflicting classifications of pathogenicity (Nov 02, 2023)
6-7541917-T-G		Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;Arrhythmogenic right ventricular dysplasia 8 • Cardiomyopathy • not specified • Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	Uncertain significance (Dec 13, 2023)
6-7541920-G-C		Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;Arrhythmogenic right ventricular dysplasia 8	Uncertain significance (Dec 14, 2023)
6-7541921-C-T		Cardiomyopathy • Cardiovascular phenotype • Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	Likely benign (Jul 19, 2023)
6-7541923-G-A		Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;Arrhythmogenic right ventricular dysplasia 8	Uncertain significance (Oct 07, 2021)
6-7541924-C-G			Uncertain significance (Mar 01, 2023)
6-7541924-C-T		Woolly hair-skin fragility syndrome • Lethal acantholytic epidermolysis bullosa • Arrhythmogenic right ventricular dysplasia 8 • Cardiovascular phenotype • Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;Arrhythmogenic right ventricular dysplasia 8 • Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	Conflicting classifications of pathogenicity (Nov 08, 2023)
6-7541927-C-G		not specified • Arrhythmogenic right ventricular dysplasia 8;Arrhythmogenic cardiomyopathy with wooly hair and keratoderma • Cardiovascular phenotype • Arrhythmogenic right ventricular dysplasia 8 • Lethal acantholytic epidermolysis bullosa • Woolly hair-skin fragility syndrome • Cardiomyopathy	Benign/Likely benign (Feb 01, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DSP	protein_coding	protein_coding	ENST00000379802	24	45143

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000222	125650	0	98	125748	0.000390

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.595	1446	1.51e+3	0.957	0.0000895	18987
Missense in Polyphen		626	709.76	0.88199		8883
Synonymous	-0.950	626	596	1.05	0.0000362	5358
Loss of Function	8.61	24	130	0.185	0.00000779	1540

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000872	0.000862
Ashkenazi Jewish	0.000599	0.000595
East Asian	0.000599	0.000544
Finnish	0.000647	0.000647
European (Non-Finnish)	0.000417	0.000334
Middle Eastern	0.000599	0.000544
South Asian	0.000196	0.000196
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Major high molecular weight protein of desmosomes. Involved in the organization of the desmosomal cadherin- plakoglobin complexes into discrete plasma membrane domains and in the anchoring of intermediate filaments to the desmosomes.
• Disease: DISEASE: Keratoderma, palmoplantar, striate 2 (SPPK2) [MIM:612908]: A dermatological disorder characterized by thickening of the skin on the palms (linear pattern) and the soles (island-like pattern) and flexor aspect of the fingers. Abnormalities of the nails, the teeth and the hair are rarely present. {ECO:0000269|PubMed:9887343}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated, with woolly hair and keratoderma (DCWHK) [MIM:605676]: An autosomal recessive cardiocutaneous syndrome characterized by a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair, and dilated left ventricular cardiomyopathy. {ECO:0000269|PubMed:11063735}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Arrhythmogenic right ventricular dysplasia, familial, 8 (ARVD8) [MIM:607450]: A congenital heart disease characterized by infiltration of adipose and fibrous tissue into the right ventricle and loss of myocardial cells, resulting in ventricular and supraventricular arrhythmias. {ECO:0000269|PubMed:12373648, ECO:0000269|PubMed:15941723, ECO:0000269|PubMed:20031617}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Skin fragility-woolly hair syndrome (SFWHS) [MIM:607655]: An autosomal recessive genodermatosis characterized by skin fragility with blistering, focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, and woolly hair with varying degrees of alopecia. {ECO:0000269|PubMed:11841538}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epidermolysis bullosa, lethal acantholytic (EBLA) [MIM:609638]: A form of epidermolysis bullosa characterized by severe fragility of skin and mucous membranes. The phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. Typical features include universal alopecia, neonatal teeth, and nail loss. Histopathology of the skin shows suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated, with woolly hair, keratoderma, and tooth agenesis (DCWHKTA) [MIM:615821]: A cardiocutaneous syndrome characterized by biventricular dilated cardiomyopathy, hyperkeratosis, woolly hair, palmoplantar keratoderma, and hypo/oligodontia. {ECO:0000269|PubMed:16628197, ECO:0000269|PubMed:20940358, ECO:0000269|PubMed:22795705}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Antiarrhythmic Pathway, Pharmacodynamics;Arrhythmogenic Right Ventricular Cardiomyopathy;Lung fibrosis;EMT transition in Colorectal Cancer;Keratinization;Developmental Biology;Neutrophil degranulation;Alpha6Beta4Integrin;Apoptotic cleavage of cell adhesion proteins;Apoptotic cleavage of cellular proteins;Innate Immune System;Immune System;Apoptotic execution phase;Apoptosis;Programmed Cell Death;EGFR1;Posttranslational regulation of adherens junction stability and dissassembly;Formation of the cornified envelope (Consensus)

Recessive Scores

• pRec: 0.370

Intolerance Scores

• loftool: 0.0770
• rvis_EVS: -2.23
• rvis_percentile_EVS: 1.32

Haploinsufficiency Scores

• pHI: 0.672
• hipred: Y
• hipred_score: 0.747
• ghis: 0.586

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.943

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Dsp
• Phenotype: digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype; cellular phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Gene ontology

• Biological process: desmosome organization;ventricular compact myocardium morphogenesis;epidermis development;peptide cross-linking;keratinocyte differentiation;keratinization;adherens junction organization;wound healing;neutrophil degranulation;skin development;intermediate filament cytoskeleton organization;intermediate filament organization;cornification;protein localization to adherens junction;bundle of His cell-Purkinje myocyte adhesion involved in cell communication;regulation of heart rate by cardiac conduction;cell-cell adhesion;regulation of ventricular cardiac muscle cell action potential
• Cellular component: cornified envelope;nucleus;cytoplasm;intermediate filament;plasma membrane;fascia adherens;intercalated disc;membrane;basolateral plasma membrane;desmosome;extracellular exosome;ficolin-1-rich granule membrane
• Molecular function: RNA binding;protein kinase C binding;structural molecule activity;structural constituent of cytoskeleton;protein binding;protein binding, bridging;cell adhesion molecule binding;cell adhesive protein binding involved in bundle of His cell-Purkinje myocyte communication;scaffold protein binding