DES in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

The role of rare variants in DES as causative mutations in Arrhythmogenic Right Ventricular Cardiomyopathy is described below. By comparing the frequency of DES variants in large ARVC clinical cohorts to the background population rate in the ExAC database, the proportion of ARVC patients with pathogenic mutations in DES can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) DES variant identified in a ARVC patient is disease-causing. Summary data for different variant classes (all protein-altering variants, loss of function truncating variants and non-truncating variants) is highlighted - see the table below for full details of this analysis.


Excess of DES variants in ARVC: 2.75% (p=0.0101)

Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in DES found in 93 ARVC samples sequenced by OMGL and in reference samples of the ExAC population database. Please note as this is based on a small ARVC cohort, the data should be used with caution.


Metrics by Variant Class:
All VarsTruncatingNon-Truncating
Excess in ARVC 2.75%
p=0.0101
-0.04%
p=1.0000
2.79%
p=0.0084
Etiological fraction 0.86
0.29 - 0.95
- 0.87
0.34 - 0.96
Odds Ratio 7.04
1.41 - 21.46
0.00
0.00 - 128.58
7.54
1.52 - 23.01

The Etiological Fraction (EF) is the proportion of affected carriers where the variant caused ARVC. The Odds Ratio (OR) describes the odds of having a rare variant in the patient cohort to the odds in the ExAC cohort. Fisher's exact test p-values are displayed for case excess, 95% confidence intervals for EFs and ORs.



SourceSamples
Tested
Variant
Type
Variants
detected
Frequency
in ARVC
Frequency
in ExAC
Case Excess
in ARVC
OMGL193All3 0.032260.004720.02754
Truncating00.000000.00036-0.00036
Non-Truncating3 0.032260.004360.02790

References

1. Roddy Walsh, Kate L. Thomson, James S. Ware, Birgit H. Funke, Jessica Woodley, Karen J. McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C. Taylor, Eric V. Minikel, Exome Aggregation Consortium, Daniel G. MacArthur, Martin Farrall, Stuart A. Cook and Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 doi:10.1038/gim.2016.90.