Gene Validity Curation

CDH2 - arrhythmogenic right ventricular cardiomyopathy

Gene: CDH2 (HGNC:1759)
Classification - 07/13/2018
Disease: arrhythmogenic right ventricular cardiomyopathy (MONDO_0016587)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy EP
Evidence Summary: There is moderate evidence that CDH2 is associated with ARVC. The first publication that associated TJP1 with ARVC was published in 2017 (28280076) and described two families: one family with five affected with p.Gln229Pro. The phenotype was consistent with ARVC. The second family was one proband with clear ARVC phenotype that carried p.Asp407Asn. A second publication in 2017 also identified in a Norwegian family the same variant, p.Asp407Asn in a family with biventricular ARVC phenotype. There is some experimental evidence in a KO mouse (15662031) that that CDH2 disruption leads to dissolution of desmosomes and area composite, cardiomyopathy, VT, and SCD. However, these are not missense variants as reported in the patients. There is emerging evidence that CDH2 mutations are associated with an ARVC phenotype, but additional information on mechanisms of disease, and pathogenicity of missense vs. truncating variants is still missing.
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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
2.5
2.5
Mayosi BM et al. 2017 Apr (PMID:28280076); Turkowski KL et al. 2017 Mar (PMID:28326674);
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
Exome/genome or all genes sequenced in linkage region 2.24 1
Mayosi BM et al. 2017 Apr (PMID:28280076);
Total Summed LOD Score 2.24    
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) 3.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
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
Kostetskii I et al. 2005 Feb 18 (PMID:15662031);
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

 


 

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 3.5 2 5.5 NO
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)
Limited
05/08/2020
EXPERT CURATION (DATE)
Limited
07/13/2018
EVIDENCE SUMMARY
There is moderate evidence that CDH2 is associated with ARVC. The first publication that associated TJP1 with ARVC was published in 2017 (28280076) and described two families: one family with five affected with p.Gln229Pro. The phenotype was consistent with ARVC. The second family was one proband with clear ARVC phenotype that carried p.Asp407Asn. A second publication in 2017 also identified in a Norwegian family the same variant, p.Asp407Asn in a family with biventricular ARVC phenotype. There is some experimental evidence in a KO mouse (15662031) that that CDH2 disruption leads to dissolution of desmosomes and area composite, cardiomyopathy, VT, and SCD. However, these are not missense variants as reported in the patients. There is emerging evidence that CDH2 mutations are associated with an ARVC phenotype, but additional information on mechanisms of disease, and pathogenicity of missense vs. truncating variants is still missing.