Gene Validity Curation

DSP - arrhythmogenic cardiomyopathy with woolly hair and keratoderma

Gene: DSP (HGNC:3052)
Classification - 07/12/2019
Disease: arrhythmogenic cardiomyopathy with woolly hair and keratoderma (MONDO_0011581)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy EP
Evidence Summary: The DSP gene was the first ARVC-gene to be associated to the disease, the initial mutation description was done in Carvajal syndrome characterized by woolly hair, keratoderma and ARVC, it is transmitted in a autosomal recessive pattern, homozygous mutations in DSP were described in in the year 2000, PMID 11063735. This was followed by the description of a heterozygous mutation in DSP in an Italian family with ARVC and clear co-segregation of the variant with the disease, PMID 12373648. These findings have been replicated worldwide in several studies performed in different ethnicities, PMID 15941723, PMID 25765472, PMID 23954618, PMID 20864495, PMID 21397041, PMID 24938629. The initial descriptions recognized also a high frequency of left ventricular compromise in families with DSP mutations, PMID 16061754, PMID 28527814. A murine model was generated able to replicate the arrhythmia phenotype and Cx43 mislocalization, PMID 22240500. A transgenic mouse overexpressing a mutant DSP had increased cardiomyocyte apoptosis, cardiac fibrosis and lipid accumulation PMID 16917092. Abnormal DSP protein expression in DSP mutation carriers has also been reported, PMID 23137101. The role of this gene in this particular disease has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time (in general, at least 3 years). No convincing evidence has emerged that contradicts the role of the gene in the specified disease. In summary, based on this overwhelming evidence, DSP is definitely associated with arrhythmogenic cardiomyopathy with woolly hair and keratoderma, maximum association score was achieved rapidly after the analysis of few main reports.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10 8 12 10
Castelletti S et al. 2017 Dec 15 (PMID:28527814);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
1
1
Castelletti S et al. 2017 Dec 15 (PMID:28527814); Rampazzo A et al. 2002 Nov (PMID:12373648);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 3.91 1
Rampazzo A et al. 2002 Nov (PMID:12373648);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.91    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Rasmussen TB et al. 2013 Jul (PMID:23137101);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Gomes J et al. 2012 Aug (PMID:22240500);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 2.5 14.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
02/03/2020
EXPERT CURATION (DATE)
Definitive
07/12/2019
EVIDENCE SUMMARY
The DSP gene was the first ARVC-gene to be associated to the disease, the initial mutation description was done in Carvajal syndrome characterized by woolly hair, keratoderma and ARVC, it is transmitted in a autosomal recessive pattern, homozygous mutations in DSP were described in in the year 2000, PMID 11063735. This was followed by the description of a heterozygous mutation in DSP in an Italian family with ARVC and clear co-segregation of the variant with the disease, PMID 12373648. These findings have been replicated worldwide in several studies performed in different ethnicities, PMID 15941723, PMID 25765472, PMID 23954618, PMID 20864495, PMID 21397041, PMID 24938629. The initial descriptions recognized also a high frequency of left ventricular compromise in families with DSP mutations, PMID 16061754, PMID 28527814. A murine model was generated able to replicate the arrhythmia phenotype and Cx43 mislocalization, PMID 22240500. A transgenic mouse overexpressing a mutant DSP had increased cardiomyocyte apoptosis, cardiac fibrosis and lipid accumulation PMID 16917092. Abnormal DSP protein expression in DSP mutation carriers has also been reported, PMID 23137101. The role of this gene in this particular disease has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time (in general, at least 3 years). No convincing evidence has emerged that contradicts the role of the gene in the specified disease. In summary, based on this overwhelming evidence, DSP is definitely associated with arrhythmogenic cardiomyopathy with woolly hair and keratoderma, maximum association score was achieved rapidly after the analysis of few main reports.