Gene Validity Curation

DES - arrhythmogenic right ventricular cardiomyopathy

Gene: DES (HGNC:2770)
Classification - 09/11/2018
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: DES: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) HGNC: 2770 MONDO_0016587 Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) Expert Panel: Arrhythmogenic Right Ventricular Cardiomyopathy SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6 Calculated Classification (date) Moderate 09/11/2018 Evidence Summary: The first publication that associated DES variants with ARVC was published in 2009 and reported a missense variant (p.Ser13Phe) in 27 individuals in five families with a severe cardiac phenotype characterized by conduction disease and right ventricular involvement (19879535). Further studies in families with ARVC have identified additional missense variants: the p.Asn342Asp variant was reported in two pedigrees (20423733); p.His326Arg in one family (24200904); p.Pro419Ser in a large Swedish pedigree (22395865) and p.Glu401Asp was detected in a family with 23 affected individuals showing predominant left ventricular arrhythmogenic cardiomyopathy with a high incidence of adverse clinical events (29212896). Two cohort studies of 91 and 22 ARVC index cases respectively have performed genetic screening of DES and identified a total of three missense variants (23168288, 20829228). Immunohistochemistry analysis of cardiac specimens from affected individuals with the p.Arg454Trp or p.Asn116Ser variant has shown severe disruption of desmin distribution at the intercalated discs and formation of cytoplasmic and perinuclear aggregates in cardiomyocytes (20423733, 20829228). Experimental data from three studies support the causative role of DES variants in ARVC (20829228, 22403400, 29212896). In particular, Klauke B et al. characterized the p.Asn116Ser variant in in vitro expression systems using a variety of methods including viscosity analysis of desmin mutant protein and atomic force microscopic imaging. Data from these experiments confirmed the presence of fibrous protein aggregates in mutant cultured cells and were consistent with histological examinations of skeletal and cardiac muscle of ARVC cases carrying the same DES variants (20829228). Similarly, functional studies on the p.Glu401Asp variant in transfected cells showed disruption of cellular adhesion and intermediate filament structure and formation of desmin cytoplasmic aggregates (29212896). Finally, the deleterious structural effects of five heterozygous DES mutations on filament formation in vitro and in living cells were investigated in a study that utilized dual color photoactivation localization microscopy (22403400). In summary, there is moderate evidence to support this gene-disease association. Desmin mutations associated with ARVC appear to be very rare and the observed phenotypes frequently overlap with dilated cardiomyopathy with conduction system abnormalities and occasionally skeletal myopathy.
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 1
2
2
Klauke B et al. 2010 Dec 1 (PMID:20829228);
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 5
2.5
2.5
van Tintelen JP et al. 2009 Nov (PMID:19879535); Otten E et al. 2010 Aug (PMID:20423733); Brodehl A et al. 2013 Dec (PMID:24200904); Bermúdez-Jiménez FJ et al. 2018 Apr 10 (PMID:29212896);
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 1.5 1.5  
Candidate gene sequencing 8.43 2
van Tintelen JP et al. 2009 Nov (PMID:19879535); Bermúdez-Jiménez FJ et al. 2018 Apr 10 (PMID:29212896);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 8.43    
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) 6
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
van Tintelen JP et al. 2009 Nov (PMID:19879535); Otten E et al. 2010 Aug (PMID:20423733); Klauke B et al. 2010 Dec 1 (PMID:20829228);
Functional Alteration Patient cells 1 0 - 2 2
2
Non-patient cells 0.5 0 - 1 8 4
Klauke B et al. 2010 Dec 1 (PMID:20829228); Bermúdez-Jiménez FJ et al. 2018 Apr 10 (PMID:29212896); Brodehl A et al. 2012 May 4 (PMID:22403400);
Models Non-human model organism 2 0 - 4 4
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) 3.5

 


 

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 6 3.5 9.5 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)
Moderate
02/04/2020
EXPERT CURATION (DATE)
Moderate
09/11/2018
EVIDENCE SUMMARY
DES: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) HGNC: 2770 MONDO_0016587 Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) Expert Panel: Arrhythmogenic Right Ventricular Cardiomyopathy SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6 Calculated Classification (date) Moderate 09/11/2018 Evidence Summary: The first publication that associated DES variants with ARVC was published in 2009 and reported a missense variant (p.Ser13Phe) in 27 individuals in five families with a severe cardiac phenotype characterized by conduction disease and right ventricular involvement (19879535). Further studies in families with ARVC have identified additional missense variants: the p.Asn342Asp variant was reported in two pedigrees (20423733); p.His326Arg in one family (24200904); p.Pro419Ser in a large Swedish pedigree (22395865) and p.Glu401Asp was detected in a family with 23 affected individuals showing predominant left ventricular arrhythmogenic cardiomyopathy with a high incidence of adverse clinical events (29212896). Two cohort studies of 91 and 22 ARVC index cases respectively have performed genetic screening of DES and identified a total of three missense variants (23168288, 20829228). Immunohistochemistry analysis of cardiac specimens from affected individuals with the p.Arg454Trp or p.Asn116Ser variant has shown severe disruption of desmin distribution at the intercalated discs and formation of cytoplasmic and perinuclear aggregates in cardiomyocytes (20423733, 20829228). Experimental data from three studies support the causative role of DES variants in ARVC (20829228, 22403400, 29212896). In particular, Klauke B et al. characterized the p.Asn116Ser variant in in vitro expression systems using a variety of methods including viscosity analysis of desmin mutant protein and atomic force microscopic imaging. Data from these experiments confirmed the presence of fibrous protein aggregates in mutant cultured cells and were consistent with histological examinations of skeletal and cardiac muscle of ARVC cases carrying the same DES variants (20829228). Similarly, functional studies on the p.Glu401Asp variant in transfected cells showed disruption of cellular adhesion and intermediate filament structure and formation of desmin cytoplasmic aggregates (29212896). Finally, the deleterious structural effects of five heterozygous DES mutations on filament formation in vitro and in living cells were investigated in a study that utilized dual color photoactivation localization microscopy (22403400). In summary, there is moderate evidence to support this gene-disease association. Desmin mutations associated with ARVC appear to be very rare and the observed phenotypes frequently overlap with dilated cardiomyopathy with conduction system abnormalities and occasionally skeletal myopathy.